Electromechanical ingestible device for delivery of a dispensable substance

ABSTRACT

Ingestible devices capable of delivering a dispensable substance, such as, for example, a therapeutic agent, as well as related components, systems and methods, are disclosed. A removably attachable storage reservoir configured to be used with an ingestible device and capable of storing dispensable substance, such as, for example, a therapeutic agent, as well as related components, systems and methods, are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Pat. Application No.16/839,107, filed on Apr. 3, 2020, now pending, entitled “IngestibleDevice For Delivery Of A Dispensable Substance;” which claims priorityto U.S. Pat. Application No. 15/699,848, filed Sep. 8, 2017, nowabandoned, entitled “Electromechanical Ingestible Device For Delivery OfA Dispensable Substance;” which claims priority under 35 U.S.C. § 119to: U.S. Provisional Pat. Application No. 62/385,553, filed on Sep. 9,2016, entitled “Electromechanical Ingestible Device for Delivery of aDispensable Substance;” U.S. Provisional Pat. Application No.62/478,955, filed on Mar. 30, 2017, and entitled “ElectromechanicalIngestible Device for Delivery of a Dispensable Substance;” U.S.Provisional Pat. Application No. 62/478,753, filed on Mar. 30, 2017, andentitled “Treatment of a Disease of the Gastrointestinal Trace with anIL-6R Inhibitor;” U.S. Provisional Pat. Application No. 62/480,187 filedon Mar. 31, 2017, entitled “Localization Systems and Method for anIngestible Device;” U.S. Provisional Pat. Application No. 62/540,873filed on Aug. 3, 2017, entitled “Localization Systems and Method for anIngestible Device;” and U.S. Provisional Pat. Application No. 62/545,129filed on Aug. 14, 2017, entitled “Treatment of a Disease of theGastrointestinal Tract with a CD40/CD40L Inhibitor.”

INCORPORATION BY REFERENCE

This application incorporates by reference the following patentapplications: USSN 14/460,893; 15/514,413; 15/680,400; 15/680,430;15/694,458; 62/376,688; 62/385,553; 62/478,753; 62/478,955; 62/434,188;62/434,320; 62/431,297; 62/434,797; 62/480,187; 62/502,383; 62/540,873;and 62/545,129.

TECHNICAL FIELD

The disclosure generally to ingestible devices capable of delivering adispensable substance, such as, for example, a therapeutic agent, aswell as related components, systems and methods. The disclosure alsogenerally relates to an attachable storage reservoir configured to beused with an ingestible device and capable of storing dispensablesubstance, such as, for example, a therapeutic agent, as well as relatedcomponents, systems and methods.

BACKGROUND

The gastrointestinal (GI) tract generally provides a therapeutic mediumfor an individual’s body. At times, therapeutic agents may need to bedispensed to specified locations within the small intestine, which ismore effective than oral administration of the therapeutic agents tocure some medical conditions. For example, therapeutic agents applieddirectly within the small intestine would not be contaminated in thestomach, and thus allow a higher dose to be delivered at a specificlocation within the small intestine. However, dispensing therapeuticagents directly within the small intestine inside a human body can bedifficult, because a device or mechanism is needed to carry thetherapeutic agents to a desired location within the small intestine andthen automatically deliver the therapeutic agent at the desiredlocation. Such a device or mechanism also needs to be operated in a safemanner as the device or mechanism needs to enter the human body.

SUMMARY

The disclosure provides ingestible devices that can deliver adispensable substance, such as, for example, a therapeutic agent withinthe GI tract of a subject. The delivery can be highly controlled. Thedelivery can be performed at a desired location with the GI tract of thesubject with relatively high accuracy. Optionally, the ingestible devicecan include a mechanism that can be used to control/manipulate theposition of the ingestible device within the GI tract of the subject.The amount of dispensable substance delivered, as well as its releaseprofile, can be controlled to a relatively high accuracy.

The disclosure also provides attachable storage reservoirs that can be,for example, configured for use with an ingestible device. The storagereservoirs can be developed so that, for example, a dispensablesubstance (e.g., a therapeutic agent) can be disposed in the storagereservoir before, during or after the storage reservoir is packaged,shipped and/or housed. With such an approach, it is possible to providea storage reservoir containing a desired dispensable substance arelatively short time period before the dispensable substance is to bedelivered. For example, the dispensable substance can be disposed withthe storage reservoir at a given point in time, and soon thereafter thestorage reservoir containing the dispensable substance can be attachedto/within the ingestible device shortly before ingestion of theingestible device.

In one aspect, the disclosure provides an ingestible device includes astorage reservoir configured to store a dispensable substance, and aforce generator component configured so that, when the force generatorgenerates a force, the dispensable substance exits the ingestible devicevia an opening in the ingestible device.

The ingestible device can include a housing.

The force generator can be at least partially disposed within thehousing.

The force generator can be completely disposed within the housing.

The storage reservoir can be at least partially disposed within thehousing.

The storage reservoir can be completely disposed within the housing.

The housing can include a first end, a second end a wall extendingbetween the first and second ends. The storage reservoir can be adjacentthe first end.

The storage reservoir can be attachable to the ingestible device.

The storage can be an integral component of the ingestible device.

The ingestible device can further include an injection device configuredso that, when the force generator generates the force, the force movesthe injection device to force the dispensable substance out of theingestible device via the opening.

The injection device can include a syringe.

The ingestible device can further include a component configured toposition the injection device at an epithelial layer and spread theepithelial layer prior to a delivery of the dispensable substance.

The injection device can be configured so that the force it generates issufficient to penetrate a mucosa membrane.

The injection device can include: a piston; a needle guide disposedwithin the storage reservoir and having an end attached to the piston; aspring connected to the needle guide; and an injection needle through aportion of the needle guide and the spring.

The spring can be configured to be compressed, and the injection needlecan be configured to extend out of the ingestible device as the pistonmoves.

The injection device can include: a truss mechanism supporting aninjection needle; and a balloon configured to expand to force the trussmechanism with the injection needle to extend out of the storagereservoir.

The injection device can include a membrane configured so that, when theforce generator generates the force, the force moves the membrane toforce the dispensable substance out of the ingestible device via theopening.

The membrane can include a piston configured so that, when the forcegenerator generates the force, the force moves the membrane to force thedispensable substance out of the ingestible device via the opening.

The ingestible device can further include an optical sensing unitconfigured to detect a reflectance from an environment external to theingestible device.

The ingestible device can include a housing, and the optical sensingunit configured to detect a reflectance from an environment external tothe housing.

The ingestible device can be configured to determine a location of theingestible device based on the reflectance detected by the opticalsensing unit.

The force generator can generate the force based on the reflectancedetected by the optical sensing unit.

The ingestible device can further include an electronic component withinthe housing, wherein the electronic component is configured to activatethe force generator.

The force generator can be adjacent the electronic component.

The ingestible device can further include a safety device configured torelieve an internal pressure within the housing.

The storage reservoir can store the dispensable substance.

The ingestible device can further include an occluder. The occlude canhave a first state in which it is configured to prevent the dispensablesubstance from exiting the ingestible device via the opening in theingestible device. The occluder can have a second state in which it isconfigured to allow the dispensable substance to exit the ingestibledevice via the opening in the ingestible device.

The occluder can include magnets.

The occluder can include a sliding pin.

The occluder can include a burst disc.

The occluder can include an enteric coating.

The occluder can include an enteric coating and a sliding pin.

The occluder can include an enteric coating and magnets.

The occluder can include a dissolvable pin.

The occluder can include a dissolvable pin and an enteric coating.

The occluder can include wax.

The wax can be in the form of a plug.

The occluder can include can further include wire leads configured tomelt the wax.

The wire leads can be configured to be activated by a power source inresponse to a command from at least one computer processor.

The occluder can be disposed within a housing of the ingestible device.

The ingestible device can further include a bellow between the forcegenerator and the storage reservoir.

The force generator can be configured to apply the force to the bellowto cause the dispensable substance to exit the opening in the ingestibledevice.

The ingestible device can further include a member in the opening of theingestible device.

The member can be in the shape of a plug.

The member can include a bioabsorable material.

The force generator can include a gas generating cell configured togenerate a gas to provide the force.

The force generator can include a pressurized gas chamber.

The force generator can include a vacuumed chamber.

The force generator can include a spring.

The force generator can include a compressed spring and a tensionedspring.

The force generator can include a gear motor.

The ingestible device can include an inlet configured to draw fluid intothe storage reservoir.

The ingestible device can further include an auger device disposedaround a portion of the gearmotor that is within the storage reservoir.The auger device can be configured to be driven by the gearmotor torotate to mix the dispensable substance and fluid drawn into the storagereservoir.

The ingestible device can further include a wiper device longitudinallyconnected to a portion of the gearmotor that is within the storagereservoir. The wiper device can be configured to be driven by thegearmotor to rotate to mix the dispensable substance and fluid drawninto the storage reservoir.

The ingestible device can further include: a helix component disposedaround a portion of the gearmotor that is within the storage reservoir;and a piston disposed at one end of the helix component. The helixcomponent can be configured to be driven by the gearmotor to rotate suchthat the piston is configured to move longitudinally along pitches ofthe helix component and towards the exit valve.

The ingestible device can include a housing configured to maintain itsmechanical integrity during use of the ingestible device.

The ingestible device can include a housing configured to maintain itsmechanical integrity when a pressure within the housing increases duringuse of the ingestible device.

The ingestible device can further include a mechanism configured toreduce a gas pressure within ingestible device.

The mechanism can include a gas absorbing material.

The mechanism can include an oxygen absorbing material.

The mechanism can include a relief valve configured to open when apressure within at least a region of the ingestible device reaches athreshold level.

The storage reservoir can include a plurality of chambers.

Each of the plurality of the chambers can be configured to store adifferent dispensable substance.

The ingestible device can be configured to release the differentdispensable substances from the ingestible device at the same time.

The ingestible device can be configured to release the differentdispensable substances from the ingestible device in a sequentialmanner.

The ingestible device can include an electronic component configured tocontrol generation of the force by the force generator to provide ametered dose of the dispensable substance to exit the opening in theingestible device.

The dispensable substance can include a therapeutic agent.

The therapeutic agent can be in at least one form selected from thegroup consisting of a powder, a granule, a liquid, and a semi-liquidgel.

The ingestible device can further include a mechanism to attach theingestible device to a wall of the GI tract of a subject.

The mechanism can include a hook which is extendable.

The hook can be retractable.

The hook can include a needle configured to pierce the wall of the GItract.

The hook can be hollow and configured to provide the dispensablesubstance to the wall of the GI tract.

The hook can include a bioresorable material.

The ingestible device can further include an enteric coating supportedby at least a portion of a housing of the ingestible device.

The ingestible device can further include an actuator.

The actuator can include a pump.

The actuator can include an osmotic pump.

The ingestible device can further include at least two different entericcoatings.

In one aspect the disclosure provides an ingestible device thatincludes: a housing; an enteric coating supported by at least a portionthe housing; and a storage reservoir in the housing. The storagereservoir can be configured to store a dispensable substance.

The housing can have an opening. In a first state of the ingestibledevice, the enteric coating can cover the opening so that the entericcoating completely prevents the dispensable substance from exiting theingestible device via the opening. In a second state of the ingestibledevice, the enteric coating can be at least partially dissolved so thatenteric coating at least partially allows the dispensable substance toexit the ingestible device via the opening.

The housing can include first and second portions. In a first state ofthe ingestible device, the enteric coating can hold the first and secondportions together. In a second state of the ingestible device, theenteric coating can be at least partially dissolved so that entericcoating at least partially releases the first and second portions fromeach other.

In one aspect, the disclosure provides an ingestible device thatinclude: a housing; an actuator located within the housing; and astorage reservoir located within the housing. The storage reservoir canbe configured to store a dispensable substance.

The actuator can include a pump.

The pump can include an osmotic pump and/or a peristalsis-driven pump.

The ingestible device can further include: a semipermeable membrane; anda pressure chamber disposed adjacent the semipermeable membrane.

The ingestible device can include: a first reagent chamber configured tostore a first reagent; a second reagent chamber configured to store asecond reagent; and a diaphragm sealing both the first reagent chamberfrom the second reagent chamber.

The diaphragm can be configured to break by a first pressure generatedby the pump so that: the first reagent enters the pressure chamber viathe semipermeable membrane; the second reagent enters the pressurechamber via the semipermeable membrane; and the first reagent interactswith the second reagent to generate a second pressure.

The ingestible device can further include a piston adjacent to thepressure chamber, wherein the piston is configured to move under theinfluence of the second pressure.

The storage reservoir can include a bellow configured to be compressedunder the influence of the second pressure.

The actuator can include: a detachable section; an osmotic pump disposedadjacent to the detachable section; and a dissolvable material attachingthe detachable section to the osmotic pump. The detachable section canbe configured to detach from the osmotic pump when the dissolvablematerial dissolves.

The ingestible device can further include a suction device configured tosuck a portion of an intestinal wall into the housing through thedispensing outlet when a portion of the ingestible device contacts awall of the GI tract of a subject.

The suction device can include a barb disc disposed inwardly within thestorage device.

The ingestible device can further include first and second entericcoatings.

The actuator can include: a first semipermeable membrane adjacent thefirst enteric coating; a first chamber adjacent the first semipermeablemembrane and storing soluble particles; and a mesh at an outlet of thefirst chamber and configured to prevent the soluble particles fromexiting the first chamber.

The actuator can be configured to generate a suction force into theingestible device when the first enteric coating dissolves.

The actuator can further include: a second semipermeable membraneadjacent the second enteric coating; a second chamber adjacent thesecond semipermeable membrane and storing soluble particles; and apiston between the second chamber and the storage reservoir. Theactuator can be configured so that, when the second enteric coatingdissolves, the piston move.

In one aspect, the disclosure provides an ingestible device thatincludes: a housing;

a first actuation component in the housing; a second actuationcomponent, both located within the housing; a first enteric coatingattached to the first actuation component; a second enteric coatingattached to the second actuation component; and a storage reservoirlocated within the housing. The storage reservoir can be configured tostore a dispensable substance, and the housing can have an opening influid communication with the storage reservoir.

The first enteric coating can be configured to dissolve when exposed toluminal fluid within a first period of time, and the second entericcoating can be configured to dissolve when exposed to luminal fluidwithin a second period of time that is longer than the first period oftime.

The actuator can include: a first semipermeable membrane adjacent thefirst enteric coating; a first chamber adjacent the first semipermeablemembrane and storing soluble particles; and a mesh at an outlet of thefirst chamber and configured to prevent the soluble particles fromexiting the first chamber.

The ingestible device can further include a suction device proximate tothe opening. The actuator can be configured to generate a suction forceinto the ingestible device when the first enteric coating dissolves.

The actuator can further include: a second semipermeable membraneadjacent the second enteric coating; a second chamber adjacent thesecond semipermeable membrane and storing soluble particles; and apiston between the second chamber and the storage reservoir. Theactuator can be configured so that, when the second enteric coatingdissolves, the piston moves toward the opening.

The ingestible device can further include an injection device having afirst end proximate to the dispensing outlet and a second end connectedto the storage reservoir. The injection device can be configured todeliver the dispensable substance when the piston is propelled towardsthe dispensing outlet.

The ingestible device can include a plurality of exit valves.

The exit valve can have a tapered sidewall.

The exit valve can have a straight sidewall.

The ingestible device can include a plurality of dispensing outletsconfigured to deliver the dispensable substance out of the housing fromthe storage reservoir.

The dispensing outlet can have a tapered sidewall.

The dispensing outlet can have a straight sidewall.

A method can include moving, by the second pressure, the travelingmember to deliver the pre-loaded dispensable substance out of theingestible device via a plurality of dispensing outlets.

The ingestible device can include a plurality of openings configured sothat, when the force generator generates a force, the dispensablesubstance exits the ingestible device via the plurality of openings.

The housing can have a plurality of openings configured to allow thedispensable substance to exit the ingestible device via the plurality ofopenings.

The ingestible device can further include: one or more processingdevices; and one more machine readable hardware storage devices storinginstructions that are executable by the one or more processing devicesto determine a location of the ingestible device in a portion of a GItract of a subject to an accuracy of at least 85%.

The ingestible device can further include one or more processingdevices; and one more machine readable hardware storage devices storinginstructions that are executable by the one or more processing devicesto determine that the ingestible device is in the cecum of a subject toan accuracy of at least 70%.

The ingestible device can further include one or more processingdevices; and one more machine readable hardware storage devices storinginstructions that are executable by the one or more processing devicesto transmit data to a device capable of implementing the data todetermine a location of the medical device in a portion of a GI tract ofa subject to an accuracy of at least 85%.

The ingestible device can further include: one or more processingdevices; and one more machine readable hardware storage devices storinginstructions that are executable by the one or more processing devicesto transmit data to an external device capable of implementing the datato determine that the ingestible device is in the cecum of subject to anaccuracy of at least 70%.

The ingestible device can further include first and second lightsources, wherein the first light source is configured to emit light at afirst wavelength, and the second light source is configured to emitlight at a second wavelength different from the first wavelength.

The ingestible device can further include first and second detectors,wherein the first detector is configured to detect light at the firstwavelength, and the second detector is configured to detect light at thesecond wavelength.

The reservoir can include a dispensable substance.

The reservoir can be configured to partially fit within the housing ofthe ingestible device.

The reservoir can be configured to entirely fit within the housing ofthe ingestible device.

The reservoir can include a housing, and the housing comprises aplastic.

The plastic can include at least one material selected from the groupconsisting of PVC, silicone and polycarbonate.

The reservoir can include a housing, and the housing comprises ametal-based material.

The metal-based material can include an alloy.

The metal-based material can include stainless steel.

The reservoir can be configured to attach to the housing of theingestible device.

The reservoir can be configured to friction fit with the ingestibledevice.

The reservoir can be configured to be held to the ingestible device viaa biasing mechanism.

The biasing mechanism can include at least one member selected from thegroup consisting of a spring, a latch, a hook, a magnet, andelectromagnetic radiation.

The reservoir can be configured to fit into a groove or a track in thehousing of the ingestible device.

The reservoir can be configured to snap fit to the ingestible device.

The reservoir can be configured to be pierced.

The reservoir can be configured to carry electronic components.

The ingestible device can satisfy FDA requirements.

The reservoir can be configured to be used with an ingestible devicedisclosed herein.

In one aspect, the disclosure provides a kit that includes: aningestible device; and a reservoir configured for use in an ingestibledevice. The reservoir can be configured to hold a dispensable substance.

The kit can further include the dispensable substance in the reservoir.

The reservoir can be a reservoir as disclosed herein.

In one aspect, the disclosure provides a method that includes deliveringa therapeutic agent to a subject using an ingestible device as disclosedherein.

The therapeutic agent can be delivered to a location in the GI tract ofa subject.

In one aspect, the disclosure provides a method that includes attachinga reservoir as disclosed herein to an ingestible device.

The method can further include disposing a therapeutic agent in thereservoir before attaching the reservoir to the ingestible device.

The method can further include, after attaching the reservoir to theingestible device, using the ingestible device to deliver thetherapeutic agent to a subject.

The therapeutic agent can be delivered to a location in the GI tract ofa subject.

The method can further include determining a location of the ingestiblemedical device in a portion of a GI tract of a subject to an accuracy ofat least 85%.

Determining the location of the ingestible device within the GI tract ofa subject can include determining reflected light signals within the GItract, wherein the reflected signals comprise light of at least twodifferent wavelengths.

The reflected signals can include light of at least three differentwavelengths.

The electromechanical ingestible device for delivery of a dispensablesubstance provides an ingestible device that has a housing, an electriccomponent, a gas-generating cell, a storage reservoir, an exit valve,and a safety device, according to some embodiments described herein. Thehousing is defined by a first end, a second end substantially oppositefrom the first end, and a wall extending longitudinally from the firstend to the second end. The electronic component is located within thehousing. The gas-generating cell is located within the housing andadjacent to the electronic component, and the electronic component isconfigured to activate the gas-generating cell to generate gas. Thestorage reservoir located within the housing, and the storage reservoirstores a dispensable substance and a first end of the storage reservoiris connected to the first end of the housing. The exit valve is locatedat the first end of the housing, and the exit valve is configured toallow the dispensable substance to be released out of the first end ofthe housing from the storage reservoir. The safety device is placedwithin or attached to the housing, and the safety device is configuredto relieve an internal pressure within the housing when the internalpressure exceeds a threshold level.

In some embodiments, the housing has a polycarbonate wall of a thicknesssubstantially sufficient to withstand an internal explosion without afracture.

In some embodiments, the safe device includes oxygen absorbing materialthat absorbs oxygen within the housing to avoid an internal explosion.

In some embodiments, the safety device includes an inert non-conductivedielectric that isolates the gas-generating cell from other componentswithin the housing.

In some embodiments, the safety device includes a relief valve placed atthe first end of the housing, and the relief valve is configured to openwhen the internal pressure inside the housing reaches the thresholdlevel.

In some embodiments, the safety device includes a rupture disc placed atthe first end of the housing, and the rupture disc is configured tobreach when the internal pressure inside the housing reaches thethreshold level.

In some embodiments, the housing is configured to breach in a controlledmanner when the internal pressure inside the housing reaches thethreshold level.

In some embodiments, the gas-generating cell is a hydrogen-generatingcell that is mounted above and sealed from the electronic component.

In some embodiments, the ingestible device has a piston adjacent to thegas-generating cell, wherein the piston is propelled to move towards thefirst end of the housing via a pressure from the gas-generating cell.

In some embodiments, the piston is integrated with the gas-generatingcell in a form of a silicone seal wrapping around the gas-generatingcell, and the gas-generating cell is movable with the piston.

In some embodiments, the storage reservoir is in a form of a bellow thatis configured to be compressed via a pressure from the gas-generatingcell.

In some embodiments, the storage reservoir includes a plurality ofchambers, and each of the plurality of the chambers stores a differentdispensable substance.

In some embodiments, the different dispensable substances are releasedat a same time via the exit valve.

In some embodiments, the different dispensable substance from each ofthe plurality of the chambers is delivered via the exit valve in asequential manner.

In some embodiments, the different dispensable substances from each ofthe plurality of the chambers is controlled by a different membrane, andthe electronic component controls the gas-generating cell to release gasto propel a membrane to deliver a respective dispensable substance.

In some embodiments, the ingestible device includes a flexible diaphragmadjacent to the gas-generating cell, wherein the flexible diaphragm isconfigured to deform towards the first end of the housing via a pressurefrom the gas-generating cell.

In some embodiments, the ingestible device includes a capillary plateplaced between the gas-generating cell and the first end of the housing,and a wax seal between the gas-generating cell and the storagereservoir, wherein the wax seal is configured to melt and thedispensable substance is pushed through the capillary plate by apressure from the gas-generating cell.

In some embodiments, the capillary plate is made up of concentric ringsof micro channels.

In some embodiments, the gas-generating cell is wrapped within a bentfoil that is configured to deform via the pressure from thegas-generating cell.

In some embodiments, the wall is configured to split into two clamshellhalves along a longitudinal axis, and the ingestible device furtherincludes a diaphragm placed along the longitudinal axis in one clamshellhalf and wrapping around the electronic component. The diaphragm isconfigured to deflect into the other clamshell half via a pressure fromthe gas-generating cell.

In some embodiments, the exit valve has an umbrella shape and the firstend of the housing has a plurality of ports under the exit valve todirect the dispensable substance out of the housing radially.

In some embodiments, the exit valve has a ring around the first end ofthe housing and has a plurality of evenly distributed ports on the ringto direct the dispensable substance out of the housing.

In some embodiments, the exit valve includes a dome slit extending outof the first end of the housing, and the dispensable substance isdelivered through the dome slit.

In some embodiments, the exit valve includes a hole at the first end ofthe first end of the housing, and the hole is sealed by a wax orsilicone material configured to break by the internal pressure fromwithin the housing.

In some embodiments, the exit valve is placed at a center of gravity atthe first end of the housing to reduce unbalanced force and rotation ofcapsule when the dispensable substance is delivered through the exitvalve.

In some embodiments, the ingestible device further includes an opticalsensing unit located proximal to the first end or the second end of thehousing. The optical sensing unit is configured to transmit anillumination towards an environment external to the housing and todetect a reflectance from the environment resulting from theillumination. The electronic component is further configured to:identify a location of the ingestible device based on the reflectance;and activate the gas-generating cell to generate gas when the identifiedlocation matches with a predefined location.

In some embodiments, the electronic component is further configured tocontrol the gas-generating cell to cause an internal pressure for ametered dose of the dispensable substance to be delivered out of thehousing based on a characteristic of the reflectance.

In some embodiments, the electronic component includes a variableresistor to control an amount of gas generated by the gas-generatingcell to meter the dose of the dispensable substance.

In some embodiments, the metered dose of the dispensable substance is aone-time dose or a systematic delivery of multiple doses.

In some embodiments, the storage reservoir stores 10 µL to 1500 µL ofthe dispensable substance.

In some embodiments, the housing includes a loading port to load thedispensable substance into the storage reservoir.

In some embodiments, the dispensable substance includes a therapeuticagent in a form of powder, granule, liquid, or semi-liquid gel.

Some embodiments described herein provide an ingestible device thatincludes a housing, an electronic component, a gas-generating cell, astorage reservoir, an injection device and a safety device. The housingis defined by a first end, a second end substantially opposite from thefirst end, and a wall extending longitudinally from the first end to thesecond end. The electronic component is located within the housing. Thegas-generating cell located within the housing and adjacent to theelectronic component, and the electronic component is configured toactivate the gas-generating cell to generate gas. The storage reservoiris located within the housing, and the storage reservoir stores adispensable substance and a first end of the storage reservoir isconnected to the first end of the housing. The injection device islocated at the first end of the housing, and the jet injection device isconfigured to inject the dispensable substance out of the housing fromthe storage reservoir. The safety device placed within or attached tothe housing, and the safety device is configured to relieve an internalpressure within the housing.

In some embodiments, the dispensable substance is released through theinjection device with a force substantially strong to penetrate a mucosamembrane.

In some embodiments, the ingestible device further includes a componentattached to an exterior of the housing, wherein the component isconfigured to position the injection device at an epithelial layer andspread the epithelial layer prior to a delivery of the dispensablesubstance.

In some embodiments, the injection device is a syringe connected to orlocated within the housing and having an injecting part extending out ofthe housing.

In some embodiments, the injection device includes an injecting outletthat is configured to penetrate an epithelial layer to inject thedispensable substance.

Some embodiments described herein provide an ingestible device thatincludes a housing, an optical sensing unit, an electronic component, agas-generating cell, a storage reservoir, a membrane, and a dispensingoutlet. The housing is defined by a first end, a second endsubstantially opposite from the first end, and a wall extendinglongitudinally from the first end to the second end. The optical sensingunit is located on a side of the housing, and the optical sensing unitis configured to detect a reflectance from an environment external tothe housing. The electronic component is located within the housing. Thegas-generating cell is located within the housing and adjacent to theelectronic component. The electronic component is configured to activatethe gas-generating cell to generate gas in response to identifying alocation of the ingestible device based on the reflectance. The storagereservoir is located within the housing, and the storage reservoirstores a dispensable substance and a first end of the storage reservoiris connected to the first end of the housing. The membrane is in contactwith the gas-generating cell and configured to move or deform into thestorage reservoir by a pressure generated by the gas-generating cell.The dispensing outlet is placed at the first end of the housing, and thedispensing outlet is configured to deliver the dispensable substance outof the housing from the storage reservoir.

In some embodiments, the dispensing outlet includes an exit valvelocated at the second end of the storage reservoir, and the exist valveis configured to allow the dispensable substance to be released out ofthe first end of the housing from the storage reservoir.

In some embodiments, the dispensing outlet has an umbrella shape and thesecond end of the housing has a plurality of ports under the exit valveto direct the dispensable substance out of the housing radially.

In some embodiments, the dispensing outlet has a ring around the secondend of the housing and has a plurality of evenly distributed ports onthe ring to direct the dispensable substance out of the housing.

In some embodiments, the dispensing outlet includes a dome slitextending out of the second end of the housing, and the dispensablesubstance is delivered through the dome slit.

In some embodiments, the dispensing outlet includes a hole at the secondend of the second end of the housing, and the hole is sealed by a wax orsilicone material configured to break by a burst of internal pressurefrom within the housing.

In some embodiments, the dispensing outlet is placed at a center ofgravity at the second end of the housing to reduce unbalanced force androtation of capsule when the dispensable substance is delivered throughthe dispensing outlet.

In some embodiments, the dispensing outlet includes an injection nozzlelocated at the first end of the storage reservoir and an injectionoutlet configured to inject the dispensable substance out of the housingfrom the storage reservoir

In some embodiments, the dispensable substance is released through thedispensing outlet with a force substantially strong to penetrate amucosa membrane.

In some embodiments, the ingestible device further includes a componentattached to an exterior of the housing, and the component is configuredto position the dispensing outlet at an epithelial layer and spread theepithelial layer prior to a delivery of the dispensable substance.

In some embodiments, the dispensing outlet is connected to a syringeconnected to or located within the housing and having an injecting partextending out of the housing, and a gas actuator is located within thehousing. The gas actuator electronically controls the syringe to injectthe dispensable substance to a location that the injecting part is incontact with.

In some embodiments, the injecting part is configured to penetrate anepithelial layer to inject the dispensable substance.

In some embodiments, the electronic component is configured toautomatically activate the gas-generating cell in response to anidentification of the location of the ingestible device without anytriggering mechanism external to the ingestible device, or anypre-programmed activation condition.

In some embodiments, the location of the ingestible device is identifiedbased on the reflectance indicative of optical characteristics of thelocation without assessing a pH level of the external environment.

In some embodiments, the location includes any of a first sectionimmediately after a pyloric sphincter, or a second section immediatelyprior to an ileocecal valve.

It should be appreciated that all combinations of the foregoing conceptsand additional concepts discussed in greater detail below (provided suchconcepts are not mutually inconsistent) are contemplated as being partof the inventive subject matter disclosed herein. In particular, allcombinations of claimed subject matter appearing at the end of thisdisclosure are contemplated as being part of the inventive subjectmatter disclosed herein. It should also be appreciated that terminologyexplicitly employed herein that also may appear in any disclosureincorporated by reference should be accorded a meaning most consistentwith the particular concepts disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings primarily are for illustrative purposes and are notintended to limit the scope of the inventive subject matter describedherein. The drawings are not necessarily to scale; in some instances,various aspects of the inventive subject matter disclosed herein may beshown exaggerated or enlarged in the drawings to facilitate anunderstanding of different features. In the drawings, like referencecharacters generally refer to like features (e.g., functionally similarand/or structurally similar elements).

FIG. 1 provides an example mock-up diagram illustrating aspects of astructure of an ingestible device 100 for delivering a dispensablesubstance, according to some embodiments described herein.

FIG. 2 provides an example diagram illustrating aspects of a mechanismfor a gas-generating cell configured to generate a gas to dispense asubstance, according to some embodiments described herein.

FIG. 3 provide example structural diagrams illustrating aspects of aningestible device 100 having a piston to push for dispensable substancedelivery, according to some embodiments described herein.

FIG. 4 provides an example structural diagram illustrating aspects of anumbrella-shaped exit valve structure as a dispensing outlet of theingestible device, according to some embodiments described herein.

FIG. 5 provides an example structural diagram illustrating aspects of aring-shaped exit valve structure as a dispensing outlet of theingestible device, according to some embodiments described herein.

FIG. 6 provides an example structural diagram illustrating aspects of adome slit as a dispensing outlet of the ingestible device, according tosome embodiments described herein.

FIG. 7 provides an example structural diagram illustrating aspects of ahole placed at one end of the housing as a dispensing outlet of theingestible device, according to some embodiments described herein.

FIG. 8 provides an example structural diagram illustrating aspects of aningestible device 100 having a bellow structure for a storage reservoirof dispensable substances, according to some embodiments describedherein.

FIG. 9 provides an example structural diagram illustrating aspects of aningestible device having a flexible diaphragm to deform for dispensablesubstance delivery, according to some embodiments described herein.

FIG. 10 provides an example structural diagram illustrating aspects ofan ingestible device having an integrated piston and gas-generating cellsuch that the gas-generating cell is movable with the piston to push fordispensable substance delivery, according to some embodiments describedherein.

FIG. 11 provides an example structural diagram illustrating aspects ofan ingestible device having a capillary to direct dispensable substancesout of the storage reservoir, according to some embodiments describedherein.

FIG. 12 provides an example structural diagram illustrating aspects ofan ingestible device having a clamshell-shaped housing and a sidewayssplit diaphragm to deform for dispensable substance delivery, accordingto some embodiments described herein.

FIG. 13 provides an example structural diagram illustrating aspects ofan ingestible device having an elastomer bladder, according to someembodiments described herein.

FIG. 14 provides example structural diagrams illustrating aspects of aningestible device using an elastomer bladder to provide the pressure todeliver the dispensable substance, according to some embodimentsdescribed herein.

FIG. 15 provides example structural diagrams illustrating aspects of aningestible device having a gear motor to dispense the dispensablesubstance out of the storage reservoir, according to some embodimentsdescribed herein.

FIG. 16 provides example structural diagrams illustrating aspects of aningestible device using an auger to dispense the dispensable substanceout of the storage reservoir, according to some embodiments describedherein.

FIG. 17 provides example structural diagrams illustrating aspects of aningestible device using a wiper to dispense the dispensable substanceout of the storage reservoir, according to some embodiments describedherein.

FIG. 18 provides example structural diagrams illustrating aspects of aningestible device using a piston to drive the wiper described in FIG. 17, according to some embodiments described herein.

FIG. 19 provides an example structural diagram illustrating aspects ofan ingestible device using osmotic pressure to dispense a dispensablesubstance, according to some embodiments described herein.

FIG. 20 provides an example structural diagram illustrating aspects ofan ingestible device using diffusion of the dispensable substance byluminal fluid, according to some embodiments described herein.

FIG. 21 provides an example structural diagram illustrating aspects ofan ingestible device having a splittable housing, according to someembodiments described herein.

FIGS. 22-24 provide example structural diagrams illustrating aspects ofanchoring mechanisms of an ingestible device to anchor the ingestibledevice to the intestine for dispensable substance delivery, according tosome embodiments described herein.

FIGS. 25-26 provide example structural diagrams illustrating aspects ofan intestinal gripper of the ingestible device to grip a portion of theintestinal wall for delivering the dispensable substance, according tosome embodiments described herein.

FIGS. 27-30 provide example structural diagrams illustrating aspects ofan expanding stent of the ingestible device to lodge the ingestibledevice at a particular location in the GI tract for dispensing,according to some embodiments described herein.

FIG. 31 provides an example structural diagram illustrating aspects ofan ingestible device having a jet delivery mechanism, according to someembodiments described herein.

FIG. 32 provides alternative example structural diagram for aningestible device having a jet delivery mechanism with enhanced usablevolume of dispensable substance, according to some embodiments describedherein.

FIG. 33 provides an example structural diagram for a jet deliverymechanism with multiple nozzles, according to some embodiments describedherein.

FIG. 34 provides an alternative example structural diagram for a jetdelivery mechanism with chemical actuation, according to someembodiments described herein.

FIG. 35 provides example structural diagrams illustrating directinjection of dispensable substance with a needle by an ingestibledevice, according to some embodiments described herein.

FIG. 36 provides alternative example structural diagrams illustrating anon-axial configuration of the injection needle for delivery, accordingto some embodiments described herein.

FIG. 37 provides an example structural diagram illustrating a non-axialconfiguration of the injection needle driven by an osmotic cell,according to some embodiments described herein.

FIG. 38 provides example structural diagrams illustrating using osmoticpressure to adhere a suction device of the ingestible device to theintestinal wall, according to some embodiments described herein.

FIG. 39 provides an example structural diagram illustrating aningestible device employing an osmotic mechanism and a suction device asillustrated in FIG. 38 , according to some embodiments described herein.

FIG. 40 provide example structural diagrams illustrating aspects oftumbling suction by an ingestible device as described in FIG. 39 ,according to some embodiments described herein.

FIG. 41 provides an example structural diagram illustrating aningestible device employing a combination of a tumbling suction andneedle injection, according to some embodiments described herein.

FIGS. 42-43 provide example structural diagrams illustrating aningestible device employing a combination of a tumbling suction andneedle injection, according to some embodiments described herein.

FIG. 44 provides an example structural diagram illustrating aspects ofan electronic component including a printed circuit board (PCB) withinthe housing of the ingestible device, according to some embodimentsdescribed herein.

FIG. 45 illustrates an ingestible device including a pre-pressurizedactuator chamber and a sliding piston, according to some embodimentsdescribed herein.

FIG. 46A illustrates a portion of an ingestible device including burstdisc in line with a nozzle portion, according to some embodimentsdescribed herein.

FIG. 46B illustrates a partial sectional view of a burst disc holder,according to some embodiments described herein.

FIG. 47 illustrates a portion of an ingestible device including entericcoating occlusion component, according to some embodiments describedherein.

FIG. 48 shows stacked layers of an enteric coating for an ingestibledevice, according to some embodiments described herein.

FIG. 49 illustrates an ingestible device including a magnetic occlusioncomponent, a burst disc, and a pre-pressurized actuator chamber,according to some embodiments described herein.

FIG. 50 illustrates an ingestible device including a magnetic occlusioncomponent and pre-pressurized actuator chamber, according to someembodiments described herein.

FIG. 51 illustrates an ingestible device including enteric slidingocclusion component and pre-pressurized actuator chamber and a slidingpiston, according to some embodiments described herein.

FIG. 52 illustrates an ingestible device including dissolvable pinocclusion component and a pre-pressurized chamber and a sliding piston,according to some embodiments described herein.

FIG. 53 illustrates an ingestible device including wax plug with wirelead activators, according to some embodiments described herein.

FIG. 54 illustrates an ingestible device including a pre-pressurizedchamber and a bellows, according to some embodiments described herein.

FIG. 55 illustrates an ingestible device including a spring actuator anda sliding piston, according to some embodiments described herein.

FIG. 56 illustrates an ingestible device including a spring actuatedslidable housing portion, according to some embodiments describedherein.

FIG. 57 illustrates an ingestible device with another spring actuatedslidable housing portion, according to some embodiments describedherein.

FIG. 58 illustrates an ingestible device including a melt away occlusioncomponent and a pressurized chamber, according to some embodimentsdescribed herein.

FIG. 59 illustrates an ingestible device including a dissolvable pinocclusion component and a spring actuated sliding piston, according tosome embodiments described herein.

FIG. 60 illustrates an ingestible device including shuttle sliderocclusion component and a pressurized chamber, according to someembodiments described herein.

FIG. 61 illustrates an ingestible device including hydrogen cellactuator and burst disc occlusion component, according to someembodiments described herein.

FIG. 62 illustrates another ingestible including hydrogen cell actuatorand burst disc occlusion component, according to some embodimentsdescribed herein.

FIG. 63 illustrates an ingestible device including a vacuum actuatorchamber and enteric coating occlusion components, according to someembodiments described herein.

FIG. 64 illustrates an ingestible device including an attachablereservoir, according to some embodiments described herein.

FIG. 65 is a view of an example embodiment of an ingestible device, inaccordance with some embodiments of the disclosure.

FIG. 66 is an exploded view of the ingestible device of FIG. 65 , inaccordance with some embodiments of the disclosure.

FIG. 67 is a diagram of an ingestible device during an example transitthrough a GI tract, in accordance with some embodiments of thedisclosure.

FIG. 68 is a diagram of an ingestible device during an example transitthrough a jejunum, in accordance with some embodiments of thedisclosure.

FIG. 69 is a flowchart of illustrative steps for determining a locationof an ingestible device as it transits through a GI tract, in accordancewith some embodiments of the disclosure.

FIG. 70 is a flowchart of illustrative steps for detecting transitionsfrom a stomach to a duodenum and from a duodenum back to a stomach,which may be used when determining a location of an ingestible device asit transits through a GI tract, in accordance with some embodiments ofthe disclosure.

FIG. 71 is a plot illustrating data collected during an exampleoperation of an ingestible device, which may be used when determining alocation of an ingestible device as it transits through a GI tract, inaccordance with some embodiments of the disclosure.

FIG. 72 is another plot illustrating data collected during an exampleoperation of an ingestible device, which may be used when determining alocation of an ingestible device as it transits through a GI tract, inaccordance with some embodiments of the disclosure.

FIG. 73 is a flowchart of illustrative steps for detecting a transitionfrom a duodenum to a jejunum, which may be used when determining alocation of an ingestible device as it transits through a GI tract, inaccordance with some embodiments of the disclosure.

FIG. 74 is a plot illustrating data collected during an exampleoperation of an ingestible device, which may be used when detecting atransition from a duodenum to a jejunum, in accordance with someembodiments of the disclosure.

FIG. 75 is a plot illustrating muscle contractions detected by aningestible device over time, which may be used when determining alocation of an ingestible device as it transits through a GI tract, inaccordance with some embodiments of the disclosure.

FIG. 76 is a flowchart of illustrative steps for detecting a transitionfrom a jejenum to an ileum, which may be used when determining alocation of an ingestible device as it transits through a GI tract, inaccordance with some embodiments of the disclosure.

FIG. 77 is a flowchart of illustrative steps for detecting a transitionfrom a jejenum to an ileum, which may be used when determining alocation of an ingestible device as it transits through a GI tract, inaccordance with some embodiments of the disclosure.

FIG. 78 is a flowchart of illustrative steps for detecting a transitionfrom an ileum to a cecum, which may be used when determining a locationof an ingestible device as it transits through a GI tract, in accordancewith some embodiments of the disclosure.

FIG. 79 is a flowchart of illustrative steps for detecting a transitionfrom a cecum to a colon, which may be used when determining a locationof an ingestible device as it transits through a GI tract, in accordancewith some embodiments of the disclosure.

FIG. 80 illustrates a tapered silicon bellows.

FIG. 81 illustrates a tapered silicone bellows in the simulated devicejig.

FIG. 82 illustrates a smooth PVC bellows.

FIG. 83 illustrates a smooth PVC bellows in the simulated device jig.

FIG. 84 demonstrates a principle of a competition assay performed in anexperiment.

FIG. 85 shows AlphaLISA data.

FIG. 86 shows AlphaLISA data.

FIG. 87 shows AlphaLISA data.

FIG. 88 illustrates a test method.

FIG. 89 illustrates an assay principle.

FIG. 90 illustrates an ingestible device.

FIG. 91 illustrates a wax valve system.

FIG. 92A illustrates a wax valve system in a closed position.

FIG. 92B illustrates a wax valve system in an open position.

FIG. 93 illustrates an ingestible device with two outlets fordispensing.

DETAILED DESCRIPTION

Following below are more detailed descriptions of various conceptsrelated to, and exemplary embodiments of, ingestible devices capable ofdelivering a dispensable substance, such as, for example, a therapeuticagent, as well as related components, systems and methods. Alsofollowing below are more detailed descriptions of various conceptsrelated to, and exemplary embodiments of, attachable storage reservoirconfigured to be used with an ingestible device and capable of storingdispensable substance, such as, for example, a therapeutic agent, aswell as related components, systems and methods.

Various systems, devices, and methods are described herein to provide anexample of at least one embodiment for the subject matter describedherein. No embodiment limits any subject matter described herein and anyclaimed subject matter may cover systems, devices, and methods thatdiffer from those described herein. It is possible that the claimedsubject matter are not limited to systems, devices, and methods havingall of the features of any one systems, devices, and methods describedherein or to features common to multiple or all of the systems, devices,and methods described herein. It may be possible that a system, device,or method described herein is not an embodiment of any claimed subjectmatter. Any subject matter disclosed in systems, devices, and methodsdescribed herein that is not claimed in this document may be the subjectmatter of another protective instrument, for example, a continuingpatent application, and the applicants, inventors or owners do notintend to abandon, disclaim or dedicate to the public any such subjectmatter by its disclosure in this document.

It will be appreciated that, for simplicity and clarity of illustration,where considered appropriate, reference numerals may be repeated amongthe figures to indicate corresponding or analogous elements. Inaddition, numerous specific details are set forth in order to provide athorough understanding of the embodiments described herein. However, itwill be understood by those of ordinary skill in the art that theembodiments described herein may be practiced without these specificdetails. In other instances, well-known methods, procedures andcomponents have not been described in detail so as not to obscure theembodiments described herein. In addition, the description is not to beconsidered as limiting the scope of the embodiments described herein.

It should be noted that terms of degree such as “substantially”, “about”and “approximately” when used herein mean a reasonable amount ofdeviation of the modified term such that the result is not significantlychanged. These terms of degree should be construed as including adeviation of the modified term if this deviation would not negate themeaning of the term it modifies.

In addition, as used herein, the wording “and/or” is intended torepresent an inclusive-or. That is, “X and/or Y” is intended to mean Xor Y or both, for example. As a further example, “X, Y, and/or Z” isintended to mean X or Y or Z or any combination thereof.

As used herein, the term “coupled” indicates that two elements can bedirectly coupled to one another or coupled to one another through one ormore intermediate elements.

As used herein, the term “body” refers to the body of a patient, asubject or an individual who receives the ingestible device. The patientor subject is generally a human or other animal.

As used herein, the term “gastrointestinal tract” or “GI tract” refersto all portions of an organ system responsible for consuming anddigesting foodstuffs, absorbing nutrients, and expelling waste. Thisincludes orifices and organs such as the mouth, throat, esophagus,stomach, small intestine, large intestine, rectum, anus, and the like,as well as the various passageways and sphincters connecting theaforementioned parts.

As used herein, the term “reflectance” refers to a value derived fromlight emitted by the device, reflected back to the device, and receivedby a detector in or on the device. For example, in some embodiments thisrefers to light emitted by the device, wherein a portion of the light isreflected by a surface external to the device, and the light is receivedby a detector located in or on the device.

As used herein, the term “illumination” refers to any electromagneticemission. In some embodiments, an illumination may be within the rangeof Infrared Light (IR), the visible spectrum and ultraviolet light (UV),and an illumination may have a majority of its power centered at aparticular wavelength in the range of 100 nm to 1000 nm. In someembodiments, it may be advantageous to use an illumination with amajority of its power limited to one of the infrared (750 nm-1000 nm),red (620 nm-750 nm), green (495 nm-570 nm), blue (450 nm-495 nm), orultraviolet (100 nm-400 nm) spectrums. In some embodiments, a pluralityof illuminations with different wavelengths may be used.

The various embodiments described herein generally relate to aningestible device that is configured to arrive at a specific locationwithin the gastrointestinal (GI) tract via oral consumption and, in someembodiments, for releasing substances including medicaments andtherapeutics at the specific location. In another embodiment, theingestible device may be used for releasing substances includingmedicaments and therapeutics in other parts of the body, such as but notlimited to the female reproductive tract, and/or the like. In someembodiments, the release of the dispensable substances may take a formsimilar to a bolus or a bust of dispensing. In some embodiments, therelease of the substances may take a form similar to systemictherapeutic agent delivery. The ingestible device may include a releasestructure that helps the substance to be delivered on the inner surface,e.g., the mucosa layer, of the GI tract, or through a penetration of themucosa layer.

FIG. 1 provides an example mock-up diagram illustrating aspects of astructure of an ingestible device 100 for delivering a dispensablesubstance, according to some embodiments described herein. In someembodiments, the ingestible device 100 may generally be in the shape ofa capsule, a pill or any swallowable form that may be orally consumed byan individual. In this way, the ingestible device 100 may be ingested bya patient and may be prescribed by healthcare practitioners andpatients.

The ingestible device 100 includes a housing 101 that may take a shapesimilar to a capsule, a pill, and/or the like, which may include twoends 102 a-b. The housing 101 may be designed to withstand the chemicaland mechanical environment of the GI tract (e.g., effects of musclecontractile forces and concentrated hydrochloric acid in the stomach). Abroad range of materials that may be used for the housing 101. Examplesof these materials include, but are not limited to, thermoplastics,fluoropolymers, elastomers, stainless steel and glass complying with ISO10993 and USP Class VI specifications for biocompatibility; and anyother suitable materials and combinations thereof. In certainembodiments, these materials may further include liquid silicone rubbermaterial with a hardness level of 10 to 90 as determined using adurometer (e.g., MED-4942™ manufactured by NuSil™), a soft biocompatiblepolymer material such as, but not limited to, polyvinyl chloride (PVC),polyethersulfone (PES), polyethylene (PE), polyurethane (PU) orpolytetrafluoroethylene (PTFE), and a rigid polymer material coated witha biocompatible material that is soft or pliable (e.g., a poly(methylmethacrylate) (PMMA) material coated with silicone polymer). Use ofdifferent materials for different components may enablefunctionalization of certain surfaces for interaction with proteins,antibodies, and other biomarkers. For example, Teflon® may be used as amaterial in the ingestible device 10 for movable components in order toreduce friction between these components. Other example materials mayinclude other materials commonly used in micro-fabrication, such aspolydimethylsiloxane (PDMS), borosilicate glass, and/or silicon.Although specific materials may be referred to herein as being used toconstruct the device for illustrative purposes, the materials recitedare not intended to be limiting, and one skilled in the art may easilyadapt the device to use any number of different materials withoutaffecting the overall operation or functionality of the device.

In some embodiments, the housing 101 of the ingestible device 100 may bemanufactured from a type of plastic, such as a photosensitive acrylicpolymer material or an inert polycarbonate material. The housing 101 mayalso be formed using material that can be sterilized by chemicals. Insome implementation, the wall of the housing 101 may have a thickness of0.5 mm-1 mm, which is sufficient to sustain an internal explosion (e.g.,caused by hydrogen ignition or over pressure inside the housing).

The housing 101 may or may not have a pH-sensitive enteric coating todetect or otherwise be sensitive to a pH level of the environmentexternal to the ingestible device. In some specific parts of the GItract, such as but not limited to sections immediately after passingthrough the pyloric sphincter, or sections immediately prior to theileocecal valve, it may be difficult to target a specific locationsolely based on the pH level. Instead of relying on the pH level, theingestible device 100 includes an optical sensing unit that transmits anillumination to the environment and collects a reflectance, based onwhich, the region-specific location of the ingestible device may beidentified based on optical characteristics of the reflectance. Forexample, the ingestible device may deliver a therapeutic agent to aspecific location within the GI tract that harbors an injury such as alesion. The specific location may be pre-determined through a previouslyconducted endoscopy. Further discussion on determining a location of theingestible device may be found in connection with FIG. 44 .

The housing 101 may be formed by coupling two enclosure portionstogether. For example, the two enclosure portions can be mated and fusedtogether with an adhesive material, such as a cyanoacrylate variant. Thehousing 101, in effect, protects the interior of the ingestible device100 from its external environment and protects the external environment(e.g., the gastrointestinal tract) from components inside the ingestibledevice 100.

The ingestible device 100 may include an electronic component within thehousing 100. The electronic component may be placed proximally to an end102 b of the housing, and includes a printed circuit board (PCB), abattery, an optical sensing unit, and/or the like. Further examplestructures of the electronic component may be illustrated in FIG. 44 .

The ingestible device 100 further includes a gas-generating cell 103that is configured to generate gas and thus cause an internal pressurewithin the housing 101. In one implementation, the gas-generating cell103 may be a hydrogen-generating cell, such as but not limited to aVarta® Hydrogen Gas-generating Cell. In another implementation, one ormore other gas-generating cells that generate an inert gas that isharmless to the human body may be used.

In some implementations, the gas-generating cell may include or beconnected to a separate channel or valve of the ingestible device suchthat gas may be release through the channel or valve to create a motionto alter the position of the ingestible device within the GI tract. Suchgas release can also be used to position the ingestible device relativeto the intestinal lining. In another implementation, gas may be releasedthrough the separate channel or valve to alter the surface orientationof the intestinal tissue prior to delivery of the dispensable substance.

A traveling plunger 104 may be placed on top of the gas-generating cell103 within the housing 101. The traveling plunger 104 is a membrane thatseparates the gas-generating cell 103 and a storage reservoir thatstores the dispensable substance 105. In some implementations, thetraveling plunger 104 may be a movable piston, as is further illustratedin FIGS. 3-4 . In some implementations, the traveling plunger 104 mayinstead be a flexible membrane such as but not limited to a diaphragm,as further illustrated in FIG. 10 . In some implementations, thetraveling plunger 104, which may have the form of a flexible diaphragm,may be placed along an axial direction of the housing 101, instead ofbeing placed on top of the gas-generating cell 103, as is furtherillustrated in FIG. 44 . The traveling plunger or the membrane 104 maymove (when the membrane 104 is a piston) or deform (when the membrane104 is a diaphragm) towards a direction of the end 102 a of the housing,when the gas-generating cell 103 generates gas to create an internalpressure that pushes the membrane 104. In this way, the membrane ortraveling plunger 104 may push the dispensable substance 105 out of thehousing via a dispensing outlet 107.

The housing 101 may include a storage reservoir storing one or moredispensable substances 105 adjacent to the traveling plunger 104. Thedispensable substance 105 may be a therapeutic or medical agent that maytake a form of a powder, a compressed powder, a fluid, a semi-liquidgel, or any other dispensable or deliverable form. The delivery of thedispensable substance 105 may take a form such as but not limited tobolus, semi-bolus, continuous, systemic, burst therapeutic agentdelivery, and/or the like.

In some implementations, the storage reservoir may include multiplechambers, and each chamber stores a different dispensable substance. Forexample, the different dispensable substances can be released at thesame time via the dispensing outlet 107. Alternatively, the multiplechambers may take a form of different layers within the storagereservoir such that the different dispensable substance from eachchamber is delivered sequentially in an order. In one example, each ofthe multiple chambers is controlled by a separate traveling plunger,which may be propelled by gas generation. The electronic component maycontrol the gas-generating cell 103 to generate gas to propel a specifictraveling plunger, e.g., via a separate gas generation chamber, etc., todeliver the respective substance. In some embodiments, the content ofthe multiple chambers may be mixed or combined prior to release, forexample, to activate the therapeutic agent.

The ingestible device 100 may include a dispensing outlet 107 at one end102 a of the housing 101 to direct the dispensable substance 105 out ofthe housing. The dispensing outlet 107 may include an exit valve (asfurther illustrated in FIGS. 5-6 ), a slit or a hole (as furtherillustrated in FIGS. 7-8 ), a jet injection nozzle with a syringe,and/or the like. When the traveling plunger 104 moves towards the end102 a of the housing 101, an internal pressure within the storagereservoir may increase and push the dispensing outlet to be open to letthe dispensable substance 105 be released out of the housing 101.

The use of a hydrogen-generating cell within an ingestible device 100may incur a variety of safety risks, which can be mitigated by properdevice design. For example, hydrogen ignition/heating within or externalto the ingestible device 100, over pressure within the housing 101,hydrogen toxicity may damage the use of the ingestible device. A safetydevice such as a pressure relief device 106 may be placed within orattached to the housing 101 to mitigate the safety risk.

In some embodiments, hydrogen ignition inside the ingestible device mayoccur if air (containing oxygen) is present inside the ingestible device100. For example, hydrogen requires very little energy to initiatecombustion, e.g., with a minimum energy for ignition in air of just0.017 mJ. When silver oxide batteries (e.g., see 131 in FIG. 3 ) areused in the ingestible device 100, the likelihood of a spark (thoughremote) cannot be eliminated and may result from inductive charges andintroduced air gap, or other scenarios.

For example, the pressure P₁ within the ingestible device 100 may beestimated based on a worst-scenario analysis of Hydrogen-Air mixture asapproximately P₁ = 1479 kPa or 215 psi. As the hydrogen concentrationwithin the ingestible device 100 may likely increase with respect totime, a sufficient concentration of hydrogen may be assumed to liebetween the Lower Explosive Limit (LEL) and Upper Explosive Limit (UEL)of 4% and 75% respectively. Thus the final pressure may be higher, giventhe initial pressure within the ingestible device may exceed 101.3 kPadue to the addition of hydrogen. Assuming the housing 101 fractures atthis maximum pressure, the amount of energy E released may be given by:

$\text{E} = \left( \frac{\text{P}_{1} - \text{P}_{0}}{\mathrm{\Upsilon}_{1} - 1} \right) \times \text{V}_{1}$

$\text{E} = \left( \frac{1479000\text{Pa} - 101300\text{Pa}}{1.4 - 1} \right) \times 0.000001\text{m}^{3} = 3.4\text{Joules}$

where V₁ denotes an approximate volume of the ingestible device. As areference, this energy translates to a 1 g mass (approximately ¼ of anassembled capsule) travelling at 82 m/s (~180 mph), or about the sameamount of energy contained in a propelled BB gun pellet, which may causeharm to the patient.

To mitigate the hydrogen ignition, in one implementation, the housing101 may be made of polycarbonate with a wall thickness of 1.6 mm, whichmay sustain a pressure of 410 psi and thus withstand the effects of aninternal explosion without fracture.

In an implementation, the interior wall of the housing 101 may be madeof (or include a layer made of) oxygen absorbing material to reduce theconcentration of oxygen (e.g., below 2%) to avoid an internal explosion.

In an implementation, an inert non-conductive liquid dielectric (such assilicone oil, food grade castor oil, wax, and/or the like) may beapplied to contain electrical connections within the ingestible device100 to isolate any possible ignition from hydrogen within the ingestibledevice 100. For example, the isolation may also reduce the risk ofhydrogen ignition external to the ingestible device, e.g., when thegenerated hydrogen from the gas-generating cell 103 mixed with anappropriate amount of air (oxygen) contained in bubbles travels alongthe GI tract, any ignition may result in an injury to the smallintestine.

In one scenario, over pressurization may happen within the ingestibledevice 100, e.g., when the dispensing outlet 107 becomes blocked orotherwise sealed from the release of hydrogen. In this case, the housing101 may have a fracture when the hydrogen gas reaches a threshold levelof pressure. For example, when the ingestible device has a volume of 500µL (the volume hydrogen may communicate with), and the hydrogen releasedcan be 40 mL, the internal pressure generated by the hydrogen can be ashigh as:

$\text{P}_{1} = \text{P}_{0} \times \frac{\text{V}_{0}}{\text{V}_{1}}$

$\text{P}_{1} = 14.7\text{psi} \times \frac{40}{0.5} = 1176\text{psi} = 8.108\text{MPa}$

The energy released via a fracture or explosion of the overpressurization may be calculated as:

$\text{E} = \left( \frac{8.108\text{MPa} - .1013\text{MPa}}{1.869 - 1} \right) \ast 5 \ast 10^{- 7} = 4.6\text{Joules}$

The amount of energy may inflict harm to the patient.

In one implementation, the housing 101 may be designed to breach orfracture in a controlled manner and thus can relieve the internalpressure. For example, when the internal pressure within a chamberfilled with the gas from the gas-generating cell 103 exceeds a thresholdlevel, the wall around the chamber may be designed to fracture or breakto relieve the pressure.

In an implementation, a pressure relief device 106 may be placed withinthe housing 101, e.g., at the end 102 a of the housing 101. For example,the pressure relief device 106 may be a pressure relief rupture discthat is configured to release content within housing 101. Thus if thedispensing outlet 107 is clogged or blocked and the pressure within thestorage reservoir exceeds a threshold level, the pressure relief device106 may be torn to release the dispensable substance out. The advantageof the pressure relief device 106 is that it may also, in part, serve toprevent upstream contamination of the dispensable substance, because theinternal pressure is relieved by directing the dispensable substance outof the housing such that the gas would not leak into the storagereservoir.

In some implementations, the housing 101 may include small holes (e.g.,with a diameter smaller than 2 mm), e.g., on the side of the housing101, or at the end 102 a to facilitate loading the dispensable substanceinto the storage reservoir. The holes, when more than two, may bepositioned axially or radially on the housing 101. The holes maysubsequently be sealed with a UV curable cyanoacrylate.

In some implementations, a feedback control circuit (e.g., a feedbackresistor, etc.) may be added to send feedback from the gas-generatingcell 103 to the electronic component such that when the internalpressure reaches a threshold level, the electronic component may controlthe gas-generating cell 103 to turn off gas generation, or to activateother safety mechanism (e.g., feedback-controlled release valve, etc.).For example, an internal pressure sensor may be used to measure theinternal pressure within the ingestible device and generate feedback tothe feedback control circuit.

FIG. 2 provides an example diagram illustrating aspects of a mechanismfor a gas-generating cell 103 configured to generate a gas to dispense asubstance, according to some embodiments described herein. As shown inFIG. 2 , the gas-generating cell 103 generates a gas 111, which canpropel the dispensable substance 105 out of the dispensing outlet 107. Avariable resistor 108 may be connected to a circuit with thegas-generating cell 103 such that the variable resistor 108 may be usedto control an intensity and/or an amount of gas 111 (e.g., hydrogen)generated by the cell 103. Specifically, the gas-generating cell 103 maybe a battery form factor cell that is capable of generating hydrogenwhen a resistor is applied. In this way, as the gas-generating cell 103only needs the use of a resistor only without any active powerrequirements, the gas-generating cell 103 may be integrated into aningestible device such as a capsule with limited energy/power available.For example, the gas-generating cell 103 may be compatible with acapsule at a size of 26 mm × 13 mm or smaller.

In some implementations, based on the elution rate of gas from the cell,and an internal volume of the ingestible device, it may take time togenerate sufficient gas 111 to deliver the substance 105, and the timerequired may be 30 seconds or longer. For example, the time to generatea volume of hydrogen equivalent to 500 µL of fluid would beapproximately 5 minutes. A longer period of time may be needed basedupon non-ideal conditions within the ingestible device, such asfriction, etc. Thus, given that the production of gas (e.g., hydrogen)may take time, gas generation may need to start prior to the ingestibledevice arriving at the site of delivery to build pressure up within thedevice. The ingestible device may then need to know when it isapproaching the site of delivery. For example, the device may startproducing gas on an “entry transition,” which is determined bytemperature, so as to produce enough gas to be close to the pressurehigh enough to deliver the dispensable substance. The ingestible devicemay then only start producing gas again when it arrives at the site ofdelivery, which will cause the internal pressure within the ingestibledevice to reach a level required by the dispensing outlet to release thedispensable substance. In addition, for region-specific delivery, theingestible device may estimate the time it takes to build up enoughpressure to deliver the dispensable substance before the ingestibledevice arrives at a specific location, to activate gas generation.

For example, for systemic delivery, when an internal volume of theingestible device is around 500 µL, a gas generation time of 2 hours, aninitial pressure of approximately 300 pound per square inch absolute(psia) may be generated, with higher and lower pressures possible. Thegenerated pressure may drop when air enters the storage reservoir, whichwas previously occupied by the dispensable substance during thedispensing process. For systemic dispensable substance delivery, a forcewith a generated pressure of approximately 100 to 360 pound per squareinch (psi) may be required for dermal penetration, e.g., to penetratethe mucosa or epithelial layer. The pressure may also vary depending onthe nozzle design at the dispensing outlet, fluid viscosity, andsurrounding tissue proximity and properties.

The gas 111 that may be generated for a continuous delivery ofdispensable substance (e.g., 1 cc H2 in 4 hours, 16 breaths per minuteat 0.5 L tidal volume) may equate to 1 cc hydrogen in approximately 2000L of exhaled air, or approximately 0.5 ppm H2, which is belowphysiologic values of exhaled hydrogen. Reducing this time to 10 minutesequates to approximately 13 ppm hydrogen. Thus, due to the length ofintestine that may be covered during this time period, the ingestibledevice may possess a higher localized value than physiologic.

FIG. 3 provides example structural diagrams illustrating aspects of aningestible device 100 having a piston to push for dispensable substancedelivery, according to some embodiments described herein. The ingestibledevice 100 may have one or more batteries 131 placed at one end 102 a ofthe housing 101 to provide power for the ingestible device 100. The PCB132 may be placed adjacent to the battery 131, and the gas-generatingcell 103 may be mounted above the PCB 132. The gas-generating cell 103may be sealed from the bottom chamber (e.g., space including 131 and132) of the ingestible device 100. A movable piston 134 may be placedadjacent to the gas-generating cell 103. In this way, gas generationfrom the gas-generating cell 103 may propel the piston 134 to movetowards the other end 102 b of the housing 101 such that the dispensablesubstance in the storage reservoir 135 can be pushed out of the housingthrough the dispensing outlet 107, e.g., the movement is shown at 136,with the piston 134 at a position after dispensing the substance. Thestorage reservoir 135 may have a volume of approximately 600 µL or evenmore dispensable substance, which may be dispensed at one shot, orgradually over a period of time.

The battery cells 131 may have a height of 1.65 mm each, and one tothree batteries may be used. The height of the piston may be reducedwith custom molded part for around 1.5 mm to save space. If thegas-generating cell 103 is integrated with the piston 134 (e.g., asfurther illustrated in FIG. 10 ), the overall height of the PCB,batteries and gas-generating cell in total can be reduced to around 5mm, thus providing more space for dispensable substance storage. Forexample, for an ingestible device of 7.8 mm in length (e.g., from end102 a to the other end 102 b), a storage reservoir 134 of approximately600 µL may be used for dispensable substance delivery. For anotherexample, for an ingestible device of 17.5 mm in length, a storagereservoir 134 of approximately 1300 µL may be used for dispensablesubstance delivery.

FIG. 4 provides an example structural diagram illustrating aspects of anumbrella-shaped exit valve structure as a dispensing outlet of theingestible device, according to some embodiments described herein. Theexit valve may be placed at one end 102 b of the housing of aningestible device (e.g., 100 in FIG. 3 ). The exit valve may include anumbrella-shaped lid 141 placed on top of one end 102 b of the housing,under which the end 102 b of the housing may include radially and evenlydistributed holes 142 around the center of the round-shaped end 102 b.When the dispensable substance is pushed out from inside the housingthrough the holes 142, the umbrella-shaped valve 141 may be lifted dueto the pressure to let the dispensable substance out of the holes 142 beradially directed through the radially distributed notches 143 on theedge of the round-shaped end 102 b of the housing. The umbrella-shapedvalve 141, which covers the delivery holes 142, may also serve to keepthe dispensing outlet holes 142 free of contaminants outside theingestible device 100. The notches 143 and the holes 142 may be radiallyand evenly distributed around a central axis of gravity based on thegeometry of the ingestible device (e.g., a cylinder shape, etc.) toreduce or avoid rotation or tilting of the ingestible device under amovement force of the dispensable substance.

FIG. 5 provides an example structural diagram illustrating aspects of aring-shaped exit valve structure as a dispensing outlet of theingestible device, according to some embodiments described herein. Thehousing 101 of the ingestible device may include a ring-shaped valve 151at a place around the housing 101 and proximal to the end 102 b of thehousing 101. The ring-shaped valve 151 may have evenly and radiallydistributed ports 157 around the ring to direct the dispensablesubstance out of the housing 101. The ring-shaped valve 151 may alsodesigned to prevent blockage from contaminants outside the ingestibledevice 100. The ring-shaped valve 151 may optionally have a number ofevenly distributed slits 153 for even distribution of the dispensablesubstance to maintain balance of the ingestible device.

FIG. 6 provides an example structural diagram illustrating aspects of adome slit as a dispensing outlet of the ingestible device, according tosome embodiments described herein. The storage reservoir of theingestible device may include a bellow 161 (further illustrated in FIG.8 ), and one end of the bellow 161 may include a dome slit 162 extendingout of the end 102 b of the housing 101. Thus, when the bellow is beingcompressed, the dispensable substance may be propelled out of the bellowthrough the dome slit 162.

In one implementation, unlike the radial distribution through the valvein FIGS. 4-5 , the bellow 161 with the dome slit 162 may be able toeject the dispensable substance at a high velocity and thus a jetdelivery may be implemented. The internal pressure generated to compressthe bellow 161 may be sufficient to generate a delivery at a velocity topenetrate a mucosa layer within the small intestine.

FIG. 7 provides an example structural diagram illustrating aspects of ahole placed at one end of the housing as a dispensing outlet of theingestible device, according to some embodiments described herein. Adelivery hole 171 may be placed at the end 102 b of the housing 101 forburst delivery. The hole 171 may be sealed with thin wax or silicone,which may be broken by a force from inside of the housing 101 such thatthe dispensable substance can be released.

In one implementation, an injection nozzle (not shown in FIGS. 6-7 ) ora syringe may be placed at one end 102 b of the housing 101 for a jetdelivery. For example, the nozzle or syringe may have an injectingneedle extending out of the dome slit 162 or the delivery hole 171. Theinjection nozzle may use osmotic pressure from luminal fluid inside thesmall intestine to drive the dispensing mechanism. The injecting needlemay be used to penetrate into a mucosa layer within the small intestine.The various delivery mechanisms described in FIGS. 4-7 may be configuredto deliver the dispensable substance out of the ingestible device eitherradially or longitudinally.

FIG. 8 provides an example structural diagram illustrating aspects of aningestible device 100 having a bellow structure for a storage reservoirof dispensable substances, according to some embodiments describedherein. A gas-generating cell 103 (similar to that described in FIGS.1-3 ) may be mounted to the PCB 132 and batteries 131. A collapsiblesilicone bellow 161 is placed on top of the gas-generating cell 103,with one end of the bellow 161 in contact with the gas-generating cell103 and the other end in contact with one end 102 b of the housing 101.Dispensable substance may be loaded into the bellow 161, which may becompressed by gas generation from the gas-generating cell 103 todispense the dispensable substance out of the housing 101. The shape ofthe bellow 161 may aid in controlled delivery. The dispensing outlet 107may use any of the exit valves described in FIGS. 4-5 , or the dome slit162 as described in FIG. 6 .

FIG. 9 provides an example structural diagram illustrating aspects of aningestible device having a flexible diaphragm to deform for dispensablesubstance delivery, according to some embodiments described herein. Theingestible device 100 may have a flexible diaphragm 165 that may deformtowards the dispensing outlet 107 when the gas-generating cell 103generates gas. The dispensable substance may then be propelled by thedeformed diaphragm out of the housing through the dispensing outlet 107.The dispensing outlet 107 shown at FIG. 9 is in the form of a ring valveas discussed in FIG. 5 , however, any outlet design described in FIGS.4-7 can be applied.

For the respective example ingestible device with the deformablediaphragm, with a total length of 7.8 mm, the ingestible device maystore and deliver approximately 600 µL of dispensable substance. Foranother example, for an ingestible device of 17.5 mm in length, theingestible device may store and deliver approximately 1250 µL ofdispensable substance.

FIG. 10 provides an example structural diagram illustrating aspects ofan ingestible device having an integrated piston and gas generating cellsuch that the gas-generating cell is movable with the piston to push fordispensable substance delivery, according to some embodiments describedherein. The ingestible device 100 may include a piston 166 that is madeup of, or is integrated with, the gas generation cell 103. Thegas-generating cell 103 may be sealed with custom silicone. In this way,the gas-generating cell 103 may move with the piston 166 when generatinggas. Contacts may be embedded in a seal 166 wrapping around thegas-generating cell 103 with leads connected to PCB 132. The movinggas-generating cell structure may allow approximately 400 µL capacityfor dispensable substance storage and delivery.

FIG. 11 provides an example structural diagram illustrating aspects ofan ingestible device having a capillary to direct dispensable substancesout of the storage reservoir, according to some embodiments describedherein. A capillary structure 169 may be placed between thegas-generating cell 103 and an end of the housing 101. The dispensablesubstance may be stored in the empty chamber 135 around thegas-generating cell 103 and within the capillary structure 169. A waxseal may be applied between the gas-generating cell 103 and thecapillary structure 169. At an appropriate time when it is identifiedthat the ingestible device is at a specific location within theintestine, the wax seal may melt, e.g., via a generated heat by the PCB132 or the gas-generating cell 103, and then the gas generation pressuremay push the dispensable substance in the chamber 135 through thecapillary plates 169 for dispensing through a dispensing outlet 107 outof the housing 101. Optionally, an exterior wax seal may be positionedbetween the capillary structure 169 and the dispensing outlet 107 toavoid leakage or early delivery.

In one example, the capillary structure 169 may include concentric ringsof capillary plates. In another example, the capillary structure 170between the storage reservoir 135 and an end of the housing 101 may bemade of a bent foil. The ingestible device 100 with the capillarystructure may have approximately 450 µL capacity of dispensablesubstance. In some implementations, additional volume may be obtained byreducing the size of PCB 132, removing one or two batteries, integratingthe gas-generating cell 103 into the PCB 132, and/or the like. Thedispensable substance volume may increase to 900 µL.

FIG. 12 provides an example structural diagram illustrating aspects ofan ingestible device having a clamshell-shaped housing and a sidewayssplit diaphragm to deform for dispensable substance delivery, accordingto some embodiments described herein. The housing 101 of ingestibledevice may include two clamshell halves 101 a-b along the long axis ofthe housing. The clamshell structure may be used to open and loaddispensable substance into the ingestible device, or to insert aseparate storage reservoir into the ingestible device. In the ingestibledevice 100 a, a diaphragm 123 may be placed along one clamshell half 101b and extend to wrap around the gas-generating cell 103. In this manner,the diaphragm 123 may act as a dam between the storage reservoir 135storing the dispensable substance and electronics 132 to protect theelectronics 132. When the gas-generating cell 103 generates a gas, aninternal pressure may deflect the diaphragm 123 into other half ofclamshell 101 a, and thus propel the dispensable substance within thestorage reservoir 135 to be released out of the housing 101. Theingestible devices 100 b-c provide different views of the sideway splitdiaphragm 123 from two different angles.

FIG. 13 provides an example structural diagram illustrating aspects ofan ingestible device having an elastomer bladder to provide the pressureto deliver the dispensable substance, according to some embodimentsdescribed herein. An elastomeric component 152 (e.g., a bladder, aballoon, etc.) can be placed in the storage reservoir 135 storing thedispensable substance such that when the elastomeric component 152expands to fill the volume of the storage reservoir 135, the dispensablesubstance can be pushed out of the ingestible device via an outlet,e.g., one or more holes 156 on the wall of the ingestible device.

The elastomeric component 152 may be made of flexible material thattakes up a small volume in its free state but able to expand to fill thevolume of the storage reservoir 135. A residual volume may exist, as theelastomeric component 152 at its free state still takes up space withinthe storage reservoir and thus reduces the volume of dispensablesubstance that can be filled into the storage reservoir 135. Forexample, as shown in FIG. 13 , the elastomeric component 152, e.g., aballoon, even at a free state, may be slightly inflated, and thus takesup a volume of 57 µL.

One or more holes 156 on the outer shell of the ingestible device 100can allow luminal fluid to be drawn into the void behind the elastomericcomponent 152. The ports of the holes 156 on the outer wall may beshaped to prevent irritation during the use the ingestible device 100,e.g., with no edges to catch any tissue within the GI tract duringtravel, and also to reduce fouling from the back filling of luminalfluid.

A wax plug can be used to seal the one or more holes 156, which can bepushed out by pressure when the dispensable substance is released.Additional coating, removable casing or decal can be added, e.g., on topof the one or more holes 156, to ensure the dispensable substance is notdispensed during handling.

FIG. 14 provides example structural diagrams illustrating aspects ofpre-loading an ingestible device having an elastomer bladder to reducethe residual volume, according to some embodiments described herein. Toreduce the residual volume and to load the ingestible device with themaximum possible dispensable substance, the elastomeric component 152can be stretched and filled by a rod 155 prior to filling the storagereservoir 154 with the dispensable substance. In this way, the freestate of the elastomeric component 152 is preloaded under tension, whichcan reduce the residual volume. One or more holes 156 on the outer shellof the ingestible device 100 can allow luminal fluid to be drawn intothe void behind the elastomeric component 152. The ports of the holes156 on the outer wall may be shaped to prevent irritation during the usethe ingestible device 100, e.g., with no edges to catch any tissuewithin the GI tract during travel, and also to reduce fouling from theback filling of luminal fluid.

In this way, when the residual volume is reduced, the payload capacityof the ingestible device can be increased, e.g., a dose of up to 800 µLcan be carried by the ingestible device. Because of the increasedpayload capacity, the overall size of the ingestible device can thus bereduced, which may be easier for a patient to administer and may alsoincrease packing density to improve distribution logistics.

FIG. 15 provides example structural diagrams illustrating aspects of aningestible device having a gear motor to dispense the dispensablesubstance out of the storage reservoir, according to some embodimentsdescribed herein. A gear motor mechanism 160 may be placed within theingestible device, with one end connected to the battery cells 131, andthe other end placed at the opposite end of the ingestible device 100.The gear motor 160 can be driven to a specific motion, e.g., rotating,etc., such that the dispensable substance in the storage reservoir canbe dispensed out of the ingestible device 100 by the motion. Thedispensable substance can be dispensed as a bolus or a gradual dose overa given time period with a variable dose rate, e.g., by adjusting thevelocity, pattern, and power of the gear motor motion. The storagereservoir 135 may carry a volume of up to 720 µL, as the gear motormechanism may need an enhanced battery system that can limit the overallpayload volume.

FIG. 16 provides example structural diagrams illustrating aspects of aningestible device using an auger to dispense the dispensable substanceout of the storage reservoir, according to some embodiments describedherein. The gear motor 160 can be equipped with an auger device aroundthe outer wall of the gear motor 160 such that the auger device can bedriven to stir or wipe the dispensable substance to be dispensed out ofthe storage reservoir.

The diameter of the auger device 161 is smaller than the diameter of thestorage reservoir such that the auger device 161 does not touch theinner wall of the ingestible device 100, to avoid any scratch or damageto the wall of the ingestible device 100. The sealing of the ingestibledevice 100 can be static between the housing of the gear motor 160 andthe body of the ingestible device 100. This can reduce the amount oftorque required to drive the auger 161, and may allow the user of asmaller gear motor 160, which can increase the available payload volumewithin the ingestible device 100.

The auger mechanism can allow the dispensable substance to be flushedout of the ingestible device 100 and to be progressively diluted as theluminal fluid is drawn into the storage reservoir. The dispensablesubstance is then delivered out of the storage reservoir at a decliningconcentration. As a result, a low residual volume of dispensablesubstance may remain within the storage reservoir, depending on thenumber of times the auger mechanism is instantiated to dispense thedispensable substance.

FIG. 17 provides example structural diagrams illustrating aspects of aningestible device using a wiper to dispense the dispensable substanceout of the storage reservoir, according to some embodiments describedherein. A wiper device 163 can be connected to the gear motor 160 suchthat the gear motor 160 rotationally drives the wiper device 163 todispense the dispensable substance. Two ports 164 a-b on the outercasing of the ingestible device 100 on either side of the wiper wouldact as inlets or outlets. The inlet (e.g., 164 a or 164 b) is configuredto allow luminal fluid to fill the void created by the moving wiper 163and regulate the resulting negative pressure. The wiper 163 isconfigured in a size that the edge of the wiper 163 substantiallytouches the inner wall of the storage reservoir to maintain a seal andproperly deliver the dispensable substance. As a result, the batter mayneed to provide a higher power to maintain the rotation of the gearmotor 160 against friction. A wax seal may be used to retain thedispensable substance while not in use. The wiper mechanism in FIG. 17is effective at delivering the entire payload (low/zero residual volume)to maximize the delivery of the dispensable substance and to minimizewaste of the substance.

FIG. 18 provides example structural diagrams illustrating aspects of aningestible device using a piston to drive the wiper described in FIG. 17, according to some embodiments described herein. A fine pitch helix 165is disposed over the gear motor 160, and a piston 166 disposed around aportion of the gear motor 160 and at one end of the helix 165. Thus,when the gear motor 160 rotates, the fine pitched helix 165 is driven torotate to cause the piston to move towards the opposite end of the helix165. As a result, the movement of the piston pushes the dispensablesubstance out of the storage reservoir.

A passive umbrella valve 167, e.g., see also 141 in FIG. 4 , can be usedat the outlet of the ingestible device 100. The pitch of the helix 165can be specified to improve control of metering the dispensing dose overtime. A low residual volume can be achieved, as the piston 166 can emptythe payload volume of the storage reservoir.

FIG. 19 provides an example structural diagram illustrating aspects ofan ingestible device using osmotic pressure to dispense a dispensablesubstance, according to some embodiments described herein. In someimplementations, osmosis may be used to increase internal pressure ofthe ingestible device in order to dispense the substance. Osmosis orluminal fluid can enter the ingestible device through a flow path 173via an inlet on the outer wall of the ingestible device. A wax plug 172may be used to keep the luminal fluid separated from the semipermeablemembrane 179 until the ingestible device is in the desired location,e.g., the wax plug can be flushed away to allow luminal fluid in to thechamber adjacent to the membrane 179. Thus, the fluid can permeatethrough the semipermeable membrane 179, which is placed at one end ofthe storage reservoir 15, to enter the storage reservoir 135.

A volume of dry salt 180 (solute) can be positioned on one side (e.g.,the side of the storage reservoir) of a semipermeable membrane 179 thatallow water from the GI fluid (solvent) to be drawn through to combineinto a solution. The solution is not able to move through the reversedirection of the semipermeable membrane 179. Thus, as more and more GIfluid is drawn into the storage reservoir 135 to form the solution,pressure can be built on the one side of the membrane 179, which can beharnessed to evacuate the dispensable substance.

When mucus and mineral “residue” (e.g., from the GI fluid) may impedewater from passing smoothly through the membrane 179, a variety ofdifferent options can be adopted. For example, a piston 171 can be usedto drive the dispensable substance out of the ingestible device. Or foranother example, as part of the dispensable substance is pushed out ofthe ingestible device due to osmotic pressure, luminal fluid can slowlyfills in the cavity within the storage reservoir 135 (as furtherdiscussed in connection with FIG. 20 ) to diffuse the remainingdispensable substance. The mixture of the diffused dispensable substancecan thus be forced out of a one-way valve.

The osmotic dispensing mechanism can be built upon a housing 176 placedinside the ingestible device. The PCB 177 can be mounted on top of thehousing 176. An insulator 175 can be placed between the PCB 177 and theflow path channel 173 to insulate the PCB 177 from any direct contactwith GI fluid. The resistor 174 may be configured to provide a low-costheating element. When the PCB 177 generates a current to pass throughthe resistor 174, the resistor 174 may generate heat such that the waxplug 172 that is placed adjacent to or proximate to the resistor maytransition from solid to liquid upon heating. Any external gastricpressure or internally generated pressure may then cause the melted waxplug 172 to be pushed out of the original position, thus allowinggastric fluid to enter the device to drive the osmotic mechanism.

The ingestible device using osmotic pressure can provide more safetyadvantage over a gas-generating cell, as the gas, usually hydrogen, canbe a combustible gas and may cause safety hazard when administered intoa human body.

FIG. 20 provides an example structural diagram illustrating aspects ofan ingestible device using diffusion of the dispensable substance byluminal fluid, according to some embodiments described herein. Variousports 181 a-b and 182 may be added to the outer wall of the ingestibledevice. These ports may be temporarily sealed, e.g., using a wax seal orenteric coating. Once activated, the ports may be opened and thedispensable substance may slowly mix into the GI tract with the luminalfluid. An elastomeric membrane 183 b filled with the dispensablesubstance may be placed within storage reservoir 135 to utilizeperistaltic pressure within the GI tract to encourage mixing of theluminal fluid with the dispensable substance. For example, the port 182may be sealed with an enteric coating or a wax plug. When the entericcoating melts or the wax plug is removed from the original position byperistaltic pressure, the luminal fluid can enter the storage reservoir135 to mix with the dispensable substance. When the ports 181 a-b areopen, luminal fluid may also enter the storage reservoir via the ports181 a-b to generate a pressure to force the elastomeric membrane 183 bto collapse to a position 183 a, and thus dispensing the dispensablesubstance mixed with the luminal fluid out of the storage reservoir 135via the port 182.

As the dispensable substance is gradually dispensed out of the storagereservoir 135, the cavity in the storage reservoir can be flushedmultiple times, e.g., by drawing in luminal fluid into the storagereservoir 135. As a result, a higher concentration of the dispensablesubstance is delivered to the GI tract at the beginning, and theconcentration may decline over time.

FIG. 21 provides an example structural diagram illustrating aspects ofan ingestible device having a splittable housing, according to someembodiments described herein. Instead of using ports on the outer wallof the ingestible device to allow luminal fluid to draw into the storagereservoir and mix with the dispensable substance, as shown in FIG. 20 ,a splittable housing 183 can be adopted with a combination of amechanical latch 186 and an enteric coating 187. At 191, the latch 186is held closed with an enteric coating 187. At 192, the enteric coatingmay dissolve when the ingestible device enters into the GI tract, andthe latch 186 releases. At 193, when the latch releases, the housing 185may split into two halves, and thus release the dispensable substance.In this way, the entire payload can be dispensed.

The release of the latch can be activated at a predetermined location,e.g., by using a melting wax plug to release the latching mechanismand/or by using the localization system to determine the location foractivation. Further discussion of localization of the ingestible devicemay be found in PCT International Application No. PCT/US2015/052500,filed on Sep. 25, 2015, which is herein expressly incorporated byreference. The splittable housing can also be actuated by osmoticpressure.

FIGS. 22-24 provide example structural diagrams illustrating aspects ofanchoring mechanisms of an ingestible device to anchor the ingestibledevice to the intestine for dispensable substance delivery, according tosome embodiments described herein. As shown in FIG. 22 , the ingestibledevice 100 can be anchored within the intestine by extending hooks 203a-d from the ingestible device 100 after it has entered the region ofinterest. At 201, as the ingestible device 100 travels along the GItract, the hooks 203 a-d are contained within the ingestible device. At202, when the ingestible device 100 determines it has arrived at alocation within the GI tract, the hooks 203 a-d can be actuated toextend outside of the ingestible device 100 to catch in the intestinalwall and hold the ingestible device 100 in the respective location. Thehooks 203 a-d can be oriented to catch the intestinal wall regardless ofthe instant orientation of the ingestible device 100. The hooks 203 a-dcan also retract, dissolve, or detach from the intestinal wall after thedispensable substance has been delivered at the anchored location.

As shown in FIG. 23 , the hooks 203 a-d could also extend radially fromthe ingestible device, and pierce into the intestinal wall to hold theingestible device 100 in place. As shown in FIG. 24 , if the extendinghooks (e.g., 203 a-b) are hollow, the hooks can be used to both anchorthe ingestible device and inject the dispensable substance into theintestinal wall.

FIGS. 25-26 provide example structural diagrams illustrating aspects ofan intestinal gripper of the ingestible device to grip a portion of theintestinal wall for delivering the dispensable substance, according tosome embodiments described herein. As shown in FIG. 25 , a piston 205 isconnected to two anchoring arms 204 a-b within the ingestible device,e.g., at 206. When internally generated pressure (e.g., by agas-generating cell or osmotic pressure as discussed throughout thisdisclosure) moves the piston 205 forward, the two anchoring arms 204 a-bcan be consequently pushed to extend out of the ingestible device andclose to grip a portion of the intestinal wall, e.g., at 207. Theanchoring arms 204 a-b (two arms are shown in FIG. 25 for illustrativepurpose), which can be two or more arms, can be arranged in a circularpattern to form a suction-like form at state 207. Alternatively, theanchoring arms 204 a-b can be arranged in a rectangular pattern for asimple construction (e.g., fewer anchoring arms may be used). Theanchoring arms 204 a-b can be made of a rigid material but with a pivotallowing the arms to close at state 207, or the anchoring arms 204 a-bcan be made of flexible metal elements that can be bent as the piston205 moves towards the outlet of the ingestible device.

As shown in FIG. 26 , an injecting needle 206 can be used with theanchoring arms 204 a-b to inject dispensable substance into theintestinal wall after a portion of the intestinal wall is gripped. Forexample, as pressure from a actuation mechanism (e.g., gas or osmoticpressure, etc.) 211 can propel the piston 205 to move towards an outletof the ingestible device, the storage reservoir 135 storing thedispensable substance 105, e.g., therapeutic agent, and a plunger 212housing the anchoring arms 204 a-b and an extendable needle 206 can allbe moved towards the outlet of the ingestible device. At state 213, theplunger 212 can move to a position that the anchoring arms 204 a-b andthe needle 206 are extended out of the ingestible device, andconsequently, the anchoring arms 204 a-b grip a portion of theintestinal wall and the needle 206 is inserted into the gripped portion.At state 214, a fluid path can be opened at one end of the plunger 212such that the dispensable substance 105 is injected via the needle 206into the intestinal wall.

FIGS. 27-30 provide example structural diagrams illustrating aspects ofan expanding stent to lodge the ingestible device at a particularlocation in the GI tract for dispensing, according to some embodimentsdescribed herein. Examples of cylindrical stents are shown in FIGS.27-28 , e.g., a solid cylinder 220 or a hollow frame stent 21, etc. Theouter surface of the stent 220-221 may be coated in patches that maydiffuse the dispensable substance into the small intestine while thestent itself protects the dispensable substance from enzymes in theluminal fluid.

In some implementations, the stent may be formed by a shape memory alloythat returns to an expanded state upon transition to body temperature.The stent may be formed by a pre-tensioned structure that expand upondissolving of an enteric coating. The stent material may also dissolveor is comprised of material that releases therapeutic agent. Expandingstent geometries, e.g., unravelling coils, or other geometries thatallow expansion of the device along the short or long axis of thecylinder 220 may be utilized. The patch may consist of an embeddedtherapeutic agent in a dissolvable matrix. The dissolvable matrix allowsfor the re-collapsing of the therapeutic agent, or the stent materialitself dissolves over time.

As shown in FIG. 29 , the stent is placed pressing or adhering a patchor other dispensable substance-dispensing object to the surface of themucosal layer. The intent is to allow dispensable substance to diffusethrough the front of the patch towards the epithelial cells whileprotecting the body of dispensable substance from degrading agents inthe luminal fluid. The outer surface of the stent may also containdissolving micro-needles to encourage delivery of the dispensablesubstance. The stent may be deployed by splitting open the ingestibledevice to allow a mechanically driven stent to expand by spring force.The stent may also inflate like a balloon when deployed. An example ofan inflatable stent inflated using osmotic pressure is shown in FIG. 30.

If the stent is in the form of a hollow cylinder, intestinal fluid canstill pass through the center of the stent and thus does not cause ablockage while the dispensable substance is being dispensed. The surfaceof the stent may include needles, hooks, or mucosal adhesives to providegrip to the intestinal wall to lodge the ingestible device to a certainlocation within the GI tract.

FIG. 31 provides an example structural diagram illustrating aspects ofan ingestible device having a jet delivery mechanism, according to someembodiments described herein. The ingestible device 100 may be a variantof the ingestible device 100 described in FIG. 1 , with the outlet 107being an injection nozzle 301. In some implementations, when thegas-generating cell 103 generates gas 302 to propel the piston 104 tomove towards the nozzle 301 such that the dispensable substance 105 canbe pushed under the pressure to break the burst disc 106 to be injectedvia the nozzle 301. To generate sufficient pressure within theingestible device for injection, an amount of 325 µL gas may be requiredto expel the dispensable substance 105. Thus the payload of thedispensable substance 105 may be limited, e.g., 300 µL maximum.

The ingestible device may be pushed away from the intestinal wall beforeinjection so that the dispensable substance 105 can penetrate thetissues.

FIG. 32 provides alternative example structural diagram for aningestible device having a jet delivery mechanism with enhanced usablevolume of dispensable substance, according to some embodiments describedherein. The nozzle 301 may be placed at the center of the ingestibledevice. Gas channels 303 may be placed longitudinally along the wall ofthe ingestible device to transport gas from the gas-generating cell 103to propel the piston 104, which is placed at an end of the ingestibledevice. The direction of piston 104 movement may be reversed, e.g., fromone end of the ingestible device towards the center of the ingestibledevice. In this way, approximately 690 uL of total gas space can be usedwithin the ingestible device, and as a result, greater force can begenerated to inject the dispensable substance to break the burst disc106. The mechanism described in FIG. 32 , with a larger pressure chamberfor gas, may be used for multiple jets, as shown in FIG. 32 .

FIG. 33 provides an example structural diagram for a jet deliverymechanism with multiple nozzles, according to some embodiments describedherein. A three-position nozzle 304 is configured with three evenlyspaced jets 305 a-c, which can balance the reaction forces of the jetdelivery and deliver the dispensable substance at three sites 305 a-c.In some implementations, a different number of nozzles, e.g., two, four,five, six, etc., may be used in a similar way as illustrated by thethree-position nozzle 304. In some implementations, a two-positionnozzle is configured with the nozzles 180 degrees apart.

In some implementations, a multi-nozzle outlet similar to 304, can beused to deliver the dispensable substance with controlled pressuredbased on factors such as but not limited to the location of the GI tractthat the ingestible device, the thickness of the mucosal wall, thenature of the dispensable substance (how deep the dispensable substanceis to be delivered into the wall of the GI tract), and/or the like. Forexample, when the dispensable substance is to be delivered locally,e.g., past the mucus and into the first layer of cells, the ingestibledevice may adjust the amount of pressure to be generated for the localdelivery. As another example, when the dispensable substance is to bedelivered systemically, e.g., to be delivered in to the submucosa, theingestible device may configure a relatively higher pressure amount forthe high velocity jet to initiate a jet delivery.

In some implementations, the ingestible device may delivery thedispensable substance in a series of release events by controlling thetiming and amount of pressure generated. For example, a pre-defineddelivery pattern may be stored at the PCT 132 (as further illustrated inFIG. 44 ) to deliver the dispensable substance in a series of deliveryevents, e.g., intermittently (e.g., every few seconds, etc.), constantlyor continuously (e.g., delivering the full payload within a few seconds,etc.). The amount of pressure to be generated by the ingestible deviceis thus pre-programmed into the PCT 132 based on the delivery pattern.

In some implementations, a microcontroller in the PCB 132 (as furtherillustrated in FIG. 44 ) may control the amount of pressure generatedfor delivery based on a matrix of delivery variables. The deliveryvariables may include, but not limited to the number of radial nozzles(e.g., 1, 2, 3, 4, 5, etc.), the design of the nozzle (e.g., shape andgeometry parameters of the nozzle, etc.), the number of release events(e.g., 1, 2, 3, 4, 5, continuous, etc.), time duration between therelease events (e.g., 5 seconds, 10 seconds, 30 seconds, 2 minutes,etc.), the range of pressure that the ingestible device is configured togenerate (e.g., 50 psi, 150 psi, 300 psi, etc.), the amount ofdispensable substance (e.g., payload 10 µl to 1500 µl, etc.), thedistance of the ingestible device from tissue or the inner wall of theGI tract (referred to as “offset distance”), and/or the like.

FIG. 34 provides an alternative example structural diagram for a jetdelivery mechanism with chemical actuation, according to someembodiments described herein. The ingestible device may use chemicalreaction of mixing one or more reagents 311-312 to generate a sufficientvolume of gas into the pressure chamber 315 to propel the piston 104 fordispensable substance delivery. The chemical reaction may be initiatedusing a combination of an enteric coating 307 on the outer wall of theingestible device, which may dissolve to expose the pump 310 in the GItract. Once exposed to the GI fluid, the pump 310 may be driven byosmosis (osmotic-driven pump) or by peristalsis (peristalsis-drivenpump, such as a physiologic peristalsis-driven pump) and may applyenough pressure to break the diaphragm seal/spring 309. When thediaphragm seal 309 is broken, a first reagent 311 that is pre-stored ina separate chamber from a second reagent 312 can get in contact with thesecond reagent 312 to initiate the chemical reaction. The reaction cancreate gas that may pass through the semipermeable membrane 179 into thepressure chamber 315. An integrated shear ring 308 is disposed on oneend of the piston 104 to stabilize the piston 104, and may release thestored energy from the pressure chamber 315 to deliver the payloadsubstance 105 through the jet nozzles 301 (two nozzles are shown forillustrative purpose).

The release of gases during chemical reactions can increase the pressurewithin the ingestible device, providing the desired drive mechanism. Thechemical reaction between acids and bases is considered as a fastreaction which can produce large amounts of gas as a product. Theaccumulation of product gas within the small capsule may provide therequired pressure for a drug delivery jet. The amount of gas andpressure can be controlled by careful selection of the reaction and thestoichiometry of the process. An ideal chemical reaction has to be fastand should not release toxic or unsafe products for in-vivo use.

The reaction between acetic acid and sodium bicarbonate may beimplemented. The products include carbonic acid and sodium acetate.Preliminary analysis of acid and base dissociation constants (pKa, pKb)of the chemical reaction indicates that the equilibrium tends to favorthe right side of reaction, producing large quotients of the productsrelative to the reactants.

Completion of the reaction involves dissociation of the reactants inwater and release of their ions.

In a low pressure aquatic environment, carbonic acid decomposes intowater and carbon dioxide in gaseous form. With the release of carbondioxide in a small container, the pressure within the container willrise providing the pressure drive needed for pushing a jet of drugtoward the target tissue. Initial analysis of the equilibrium constant(KC and KP) and Henry’s law for gases, suggest that, with sufficientcarbonic acid production, carbon dioxide is released into the closedchamber adequate to meet the pressure requirements.

In an aquatic environment carbonic acid will also dissociate and releaseprotons. The rate of dissociation of carbonic acid, is a function ofalkalinity of the solution and the partial pressure of the released gas.

The above described reactions are reversible reactions suggesting thatwith an increase in the ratio of the products to the reactants, the rateof reaction will decrease. In addition to the stoichiometric ratios, thepartial pressures of the products can also affect the rate and directionof reaction. The release of multiple ions, limitations on ionization andsolubility of the reactants and products, and impacts of the changes inpressure make the chemical drive system a complicated environment tomodel. As a result, careful selection and analysis of the stoichiometricratios, molarities of acid and size of the chamber is needed before anefficient and safe chemical drive system is implemented.

As an example, the ingestible device may have a 400 µl of payload 105,50% of which by volume is acetic acid in water combining with drycarbonate. The ingestible device may need a 165 µl pressure chamber 315and a 30 µl of reagents 312. Moving the 30 µl reagent with an osmoticpump at 100 pound-force per square inch (PSI) may require less than 1 µlof salt for the osmotic pump 310 having a 4 mm-diameter osmoticmembrane.

FIG. 35 provides example structural diagrams illustrating directinjection of dispensable substance with a needle by an ingestibledevice, according to some embodiments described herein. The ingestibledevice may include a single needle 317 that is housed within a needleguide 318, or an array of needles (now show in FIG. 35 ), which may beextended out of and retracted back inside the ingestible device. One endof the needle guide 318 is placed within a piston 316.

At state 321, the needle 317 is inside the ingestible device and thepiston 316 is in a home position at one end of the storage reservoir. Atstate 322, when the ingestible device is actuated, e.g., by agas-generating cell generating gas, the piston 316 moves towards anoutlet of the ingestible device. The friction between the piston 316 andthe needle guide 318 is higher than the impedance force at the innerwall of the ingestible device, so that the needle 317 advances out ofthe ingestible device. A spring 319 can be compressed at the axial endof the ingestible device to allow the needle 317 to extend out of theingestible device. At state 323, once the spring 319 is fully collapsed,the pressure from the gas-generating cell may keep building up to alevel sufficient to overcome the static friction between the piston 318and the needle guide 318 so that the piston 316 keeps moving towards theoutlet of the ingestible device and thus expose dispensable substance tothe end of the needle 317 that is still inside the ingestible device. Inthis way, the substance can be dispensed through the needle 317 (with ahollow center) when the piston keeps moving. At state 324, after thedispensing, the gas-generating cell is turned off. Spikes may be placedat the inner wall at one end 325 of the ingestible device to punctureholes in the piston 316 when the piston 316 reaches the end 325. Afterthe holes are punched, the pressure on the two sides of the piston 316may be balanced and the spring 316 may drive the piston 316 and needle317 back into a retracting position, e.g., the needle 317 within theingestible device.

FIG. 36 provides alternative example structural diagrams illustrating anon-axial configuration of the injection needle for delivery, accordingto some embodiments described herein. A radial version of the directinjection as described in FIG. 35 is illustrated in FIG. 36 , by using aballoon 336 (similar to a catheter balloon) filled with the dispensablesubstance and placed inside the ingestible device. A flexible truss orlinkage mechanism 334 a-334 b and 332 a-b can be used to support aneedle 333 to be moved out of the ingestible device. At state 331, whenthe balloon 336 is deflated, the needle and the linkage mechanism 332a-b and 334 a-b are within the ingestible device. At state 332, when theballoon 336 is activated, e.g., by gas generated by a gas-generatingcell, the two nodes of the linkage mechanism 332 a-b may be propelled tomove towards each other because of the deformation of the balloon 336.As a result, the truss 334 a-b with the needle 333 may be forced out ofthe ingestible device. At state 333, when the balloon keeps deforming336 and thus further pushes the truss 334 a-b, the needle 333 may bepushed out to inject the dispensable substance from the ingestibledevice to the GI tract.

A gear motor or optionally a piston driven by either osmosis or a gascell can be used to inflate the balloon 336. FIG. 37 provides an examplestructural diagram illustrating a non-axial configuration of theinjection needle driven by an osmotic cell, according to someembodiments described herein. An osmotic cell 337 can be used togenerate pressure to inflate the balloon 336. Once the balloon 336 isinflated, the needle may deliver the substance out of the ingestibledevice in a similar manner as discussed in FIG. 36 .

FIG. 38 provides example structural diagrams illustrating using osmoticpressure to adhere a suction device of the ingestible device to theintestinal wall, according to some embodiments described herein. Theingestible device 100 may have an osmotic mechanism that has a chamber342 storing salt crystals. The chamber 342 includes a mesh 341 placed inproximate to a burst valve 340 at one end of the chamber 342, and areverse osmosis (RO) membrane 343 placed in proximate to a valve 345 onthe other end of the chamber 342. A suction device, e.g., two or moresuction fingers 347 a-b (two fingers are shown in FIG. 38 forillustrative purpose), is placed outside of the chamber 342, with anopen outlet exposed to luminal fluid in the GI tract.

At state 351, the osmotic mechanism is inactivated, e.g., the valve 345is closed so that no luminal fluid is drawn into the osmotic chamber342. At state 352, when the osmotic mechanism is activated by openingthe valve 345, luminal fluid enters the ingestible device 100 through anoutlet of the suction device 347 a-b and enters the osmotic chamber 342through the valve 345. The salt in the chamber 342 is then dissolvedinto the fluid. The RO membrane 343 prevent any fluid to flow in thereverse direction, e.g., from inside the chamber 342 to the valve 345.The fluid continues to flow, e.g., through the flow path 346, until allthe salt contained in the chamber 342 is dissolved or until intestinaltissue is drawn into the suction device 347 a-b. As luminal fluid keepsflowing into the chamber 342, the solution of the luminal fluid withdissolved salt in the chamber 342 may reduce osmotic pressure such thatthe suction force at 347 a-b may also be reduced. In this way, suctionof the intestinal tissue may stall before the tissue is in contact withthe valve 345 to avoid damage to the intestinal tissue. If the valve 340is a burst valve, when more and more luminal fluid enters into thechamber 342, the luminal fluid may eventually break the burst valve 340and osmotic flow may reverse, actively pushing the intestinal tissue outof the suction device 347 a-b. The mesh 341 placed in proximate to theburst valve 340 may prevent the salt crystals from exiting the chamber342.

FIG. 39 provides an example structural diagram illustrating aningestible device employing an osmotic mechanism and a suction device asillustrated in FIG. 38 , according to some embodiments described herein.The ingestible device 100, as shown in FIG. 39 , an outlet 107 is placedat one end of the ingestible device 100. A suction device, e.g., two ormore suction fingers 347 a-b (similar to those depicted in FIG. 38 ), isdisposed in proximate to the outlet 107. The outlet 107 is in connectionwith a storage reservoir 135 storing the dispensable substance (e.g.,therapeutic agent) 105. The storage reservoir 135 is in contact with apiston 363 (similar to 104 in FIG. 1 ), which can be propelled bypressure generated from the osmotic pump 362 to move towards the outlet107. The osmotic pump 362 is similar to the osmotic mechanism describedin FIG. 38 . A breakaway section 361 is placed in proximate to the otherend (opposite to the end where the outlet 107 is disposed) of theingestible device 100, as further described in FIG. 40 .

FIG. 40 provide example structural diagrams illustrating aspects oftumbling suction by an ingestible device as described in FIG. 39 ,according to some embodiments described herein. As shown in FIG. 39 ,the ingestible device 100 does not require any electronics or otheractuation elements. As shown in FIG. 40 , the ingestible device 100 mayconstantly, intermittently, or periodically tumble when travellingthrough the intestine 370. When the ingestible device tumbles to aposition that the outlet 107 is in direct contact with the intestinalwall 371, a suction process similar to that described in FIG. 38 mayoccur. Additional structural elements such as fins, flutes or the likemay be added to the outer wall of the ingestible device 100 to promotethe tumbling motion.

As shown in FIG. 40 , when the ingestible device 100 tumbles fromposition 372 a or 372 b to position 372 c, the axial end, e.g., theoutlet 107, contacts the intestinal wall 371 with some pressure. Theamount of pressure may push a small amount of tissue of the intestinalwall 371 to enter the outlet 107, such that the inward-pointing suctionfingers 347 a-b may latch onto the intestinal wall 371. At position 372d, the breakaway section 361, which is pre-fixed at one end of theingestible device using an enteric coating or glucose based retainingfeature, may be removed from the ingestible device 100 to expose theosmotic pump 362, as the enteric coating or glucose can dissolve in theGI tract.

FIG. 41 provides an example structural diagram illustrating aningestible device employing a combination of a tumbling suction andneedle injection, according to some embodiments described herein. Asshown in FIG. 41 , the ingestible device includes an inward barb disc347 hosting a number of suction fingers/barbs (e.g., similar to 347 a-bas shown in FIG. 39 ). A diaphragm spring 319 is connected to one end ofa storage reservoir of the ingestible device, and one end of a needle317 is connected to the spring 319. The other end of the needle 317 ishoused within a piston 316 at the other end of the storage reservoir.The piston is located proximate to an osmotic cell 363, which is similarto the osmotic pump 362 in FIG. 39 . The dissolving material 361 issimilar to the breakaway device 361 in FIG. 39 .

Therefore, as the ingestible device enters and travels along theintestine, which the dissolving material 361 may dissolve and thusexpose the osmotic cell 362 to the luminal fluid. The osmotic cell 362may then generate osmotic pressure to propel the piston 316 to movetowards the inward barb disc 347. In the meantime, the ingestible devicemay suck a portion of the intestinal tissue by the inward barb disc 347,e.g., in a similar manner as described in FIG. 40 . The needle 317 maythen, when the piston 316 keeps moving due to the osmotic pressure,extend into the intestinal tissue grabbed by the inward barb disc 327,and inject the dispensable substance into the intestinal tissue. Theneedle movement and injection process may be similar to that describedin FIG. 35 .

FIGS. 42-43 provide example structural diagrams illustrating aningestible device employing a combination of a tumbling suction andneedle injection, according to some embodiments described herein. Theosmotic mechanism described in FIG. 38 may be combined with anosmotically driven piston 363, a statically positioned needle 317 thathas a hollow center and is exposed to the dispensable substance storedin the storage reservoir 135, and two enteric coatings 371 a-b to injecta dispensable substance into the intestinal wall.

The ingestible device has an empty chamber 375 connected to a suctiondevice 347 for the luminal fluid to draw into. The inner wall of theempty chamber 375 may be covered by short-delay enteric coating 371 b.As shown in FIG. 43 , at state 401, the ingestible device, similar tothat described in FIG. 42 , may enter into the intestine. At state 402,the short-delay enteric coating 371 b may break down and thus allowluminal fluid to contact the semipermeable membrane 343 b. Water is thendrawn into the salt chamber 342 b from the luminal fluid in the chamber375, and then released out of the slat chamber 342 b by breaking theburst valve 340. A mesh screen 341 prevents whole salt crystals frombeing released outside the ingestible device. In this way, as waterkeeps being drawn from the luminal fluid in chamber 375, the osmoticactuation draws more luminal fluid into the chamber 375, and tissue ofthe intestinal wall may be sucked into the chamber 375 by the suctiondevice 347. The suction device 347, when drawing the intestinal tissue,can also anchor the ingestible device to the intestinal wall. The needle317 may pierce into the grabbed tissue of intestinal wall.

At state 403 in FIG. 43 , after tissue of the intestinal wall has beengrabbed by the suction device 347, the long-delay enteric coating 371 a,which is placed at an end of the ingestible device, may break down andallow luminal fluid to contact the semipermeable membrane 343 a placedin proximate to the end of the ingestible device. Water is then drawninto the salt chamber 342 a, and actuates a piston 363 by creatingosmotic pressure. The piston 363 then pushes the dispensable substanceout of the storage reservoir 135 via the needle 317 into the intestinaltissue grabbed by the suction device 347.

After the dispensable substance payload is fully released from thestorage reservoir 135, osmotic pressure will build behind the piston 363within the storage reservoir. This pressure can be used to retract theneedle 317 or expand the suction device 347 opening to release thetissue of the intestinal wall. Alternatively, after a period, after thedispensable substance has been delivered and the piston 363 is pushed tothe end of the storage reservoir 135, the ingestible device maynaturally detach from the intestinal wall and can then be safely passed.The needle 317 and barbs of suction device 347 are located within theingestible device and cannot contact the intestinal wall without vacuum.

The example ingestible device shown in FIG. 42 may deliver 400µl ofpayload dispensable substance, with a reduced total size as compared tothat having a gas-generating cell and a gas chamber.

The hooks, stents, needles, barbs, suction devices or the like, shownthroughout FIGS. 1-43 , may be made of bioresorbable or biodegradablematerials, such as, but not limited to polyglycolide, poly-L-lactic acid(PLLA), poly-L-D-lactic acid (PLDA), Poly ε-caprolactone-Poly LacticAcid (PCL-PLA) blends and alloys, polyorthoester (POE), poly(DL-lactide)(PDLLA), poly(lactide-co-glycolide)(PLGA), polydioxanone (PDS),polycaprolactone (PCL), Poly (alkyl cyanoacrylates) (PCA),Polyanhydrides, Poly(ortho esters), or any bioresorbable polymer withsuitable material properties such as the degradation rates and rigidityto hook, grab, pierce into, or grip the intestinal wall and may dissolveor be absorbed in the human body after an amount of time.

FIG. 44 provides an example structural diagram illustrating aspects ofan electronic component including a PCB within the housing of theingestible device, according to some embodiments described herein. ThePCB 132 may take a form that fit into the ingestible device and wraparound the gas-generating cell. In one example, when the PCB 132 has aseparate battery cell 131, the overall height of the PCB 132 may besubstantially 19 mm. In another example, the PCB 132 may achieve areduced height of 14 mm with an integrated gas-generating cell 131,which may further reduce the height of the PCB 132 to be under 10 mm. Inthis way, the PCB design may save space for the storage reservoir.

In some embodiments, the PCB 132 may include (but is not limited to) anycombination of a microcontroller, an optical sensing unit, a powersupply (such as a battery 131), a communication unit, communicationperipherals to connect the different components, and/or the like.

In some embodiments, the microcontroller includes programming, controland memory circuits for holding and executing firmware or software, andcoordinating all functions of the ingestible device (e.g., see 100 inFIG. 1 ) and the other peripherals embedded on the PCB 132. For example,the microcontroller may be implemented using a 32-bit microcontroller,such as the STM32 family of microcontrollers from STMicroelectronics™,although any suitable microcontroller may be used.

In some embodiments, the communication unit can receive operatinginstructions from an external device, such as a base station (e.g., aninfrared transmitter and/or receiver on a dock). The base station may beused for initially programming the ingestible device (e.g., 100 in FIG.1 ) with operating instructions and/or communicating with the ingestibledevice 10 during operation in real-time or after the ingestible deviceis retrieved from the body. In some embodiments, the communication unitdoes not receive any operating instructions from an external device, andinstead the ingestible device operates autonomously in vivo.

In another embodiment, endoscopic tattooing may be used to mark oridentify a location of disease (e.g., luminal digestive tract lesions)or an upstream of a disease. The identification of the specific locationof disease may in turn trigger an operation of the ingestible device.For example, the optical sensing unit may detect the presence of anendoscopic tattoo (e.g., a green dye) administered during an earlierprocedure, which may trigger the release of a therapeutic at or near thedisease site by activating gas generation of the gas-generating cell.

In other embodiments, a triggering mechanism or marker such as astainless steel clip or a magnet may be used to mark or identify sitesof disease. For example, the mechanism may trigger an operation of theingestible device, e.g., the magnet may open a valve on the ingestibledevice such that the dispensable substance may be delivered. The localtriggering mechanism (e.g., endoscopic tattooing) may not necessarily befor region-specific delivery of dispensable substances, such as, forexample, therapeutic agents.

In some embodiments, the communication sub-unit can include an opticalencoder, such as an infrared emitter and receiver. The IR emitter andreceiver can be configured to operate using modulated infrared light,i.e. light within a wavelength range of step 850 nm to 930 nm.Furthermore, the IR receiver may be included in the ingestible devicefor receiving programming instructions from the IR transmitter at thebase station and the IR transmitter may be included in the ingestibledevice for transmitting data to the IR receiver at the base station.Bidirectional IR communication between the ingestible device and thebase station can therefore be provided. It will be understood that othertypes of optical encoders or communication sub-units can be used in someembodiments; for example, some communication sub-units may utilizeBluetooth, radio frequency (RF) communications, near fieldcommunications, and the like, rather than (or in addition to) opticalsignals.

The optical sensing unit can be placed on the PCB at a position that ison the side of the housing of the ingestible device. The optical sensingunit may include various sensors to obtain in vivo information while theingestible device is in transit inside the body. Various sensors, suchas radial sensors around the housing of the ingestible device and axialsensors along the axis of the ingestible device, can be provided atdifferent locations of the ingestible device to help identify where theingestible device may be within the body. In some embodiments, the dataprovided by the sensors can be used for triggering an operation of theingestible device, e.g., to trigger the gas-generating cell (e.g., 103in FIG. 3 ) to start generating gas. Each sensor can include anilluminator that can generate an illumination to an external environmentof the ingestible device, and a detector that can detect a reflectancefrom the environment in response to the generated illumination. Thereflectance may be transmitted to the microcontroller via thecommunication peripherals on the PCB 132, to identify a specificlocation of the ingestible device.

For example, the optical sensing unit may include sensors with aninfrared Light-Emitting Diode (IR-LED) as an illuminator, and a detectorsensitive to illumination in the infrared spectrum. The sensors may, insome embodiments, include a yellow-green LED emitting light having awavelength of approximately 571 nm as an illuminator. In someembodiments, the sensors may comprise a green LED emitting light havinga wavelength of approximately 517 nm and a red LED emitting light havinga wavelength of approximately 632 nm. In some embodiments, the sensorsmay include an RGB LED package capable of emitting illumination at aplurality of different wavelengths.

In some embodiments, the sensors may include collimated light sources.The collimated light sources can orient reflective light in order tomaximize reflectance from certain external environments, such asanatomies that are circular in shape. For example, the illumination maybe provided by collimated light sources, which may be provided using LEDbinning or supplemental lenses, or by a combination of collimated andnon-collimated light sources.

The detected reflectance in response to the illumination may be used todetermine by the microcontroller a location of the ingestible device inthe GI tract. In this way, the ingestible device may keep track of acurrent region of the gastrointestinal tract surrounding the device, andmonitor the environment around the device to determine changes from oneregion to another. In some embodiments, the ingestible device mayautonomously identify a location of the device within thegastrointestinal tract of a body by monitoring the changes from oneregion to another. In some embodiments, the ingestible device mayfunction as a state machine, wherein the state tracks the currentportion of the gastrointestinal tract where the ingestible device islocated. The ingestible device may distinguish between various locationsincluding a starting point outside the body, a stomach, a duodenum, ajejunum, a caecum, a large intestine, and an exit point outside thebody. In some embodiments the ingestible device may distinguish onlybetween a stomach, a small intestine, (e.g., a small intestine which mayinclude the duodenum and the jejunum), and a large intestine (e.g., alarge intestine which may include the caecum, and the large intestine).In some embodiments, the ingestible device may distinguish between asubset of the above mentioned locations, and/or a combination of theabove locations and other locations, such as a mouth, an ileum, or arectum.

In some embodiments, the ingestible device may transmit illumination ata first wavelength towards an environment external to a housing of theingestible device, detect the resulting reflectance, and store areflectance value in a data set based on the first reflectance. Forexample, the ingestible device may transmit illumination at a redwavelength, detect a red reflectance, and store a reflectance value in ared data set that indicates how much light was measured in the redreflectance. The ingestible device may repeat this process for a numberof other types of illumination at other wavelengths, such as blue,green, or infrared wavelengths. The ingestible device may keep track ofreflectance data gathered from reflectance sensors (i.e., radialdetectors) in each of the red, green, blue and IR spectra.

This data may then be used by an onboard microprocessor to perform alocalization algorithm that identifies a pyloric transition from stomachto the duodenum portion of the small intestine; a treitz transition fromthe duodenum to the jejunum; an ileocaecal transition from the ileum(i.e., the area located at the end of the jejunum) to the caecum; and acaecal transition from the caecum to the rest of the large intestine.This can be accomplished by using a plurality of different wavelengthsof light, measuring the different amounts of light reflected by theenvironment around the device, and determining the location of thedevice in view of the different optical absorption properties of thedifferent regions of the gastrointestinal tract. The ingestible devicemay gather this data at periodic intervals, and in some embodiments,these may be spaced one second to 10 minutes apart. For example, theingestible device may intermittently, constantly or periodically detecta location of the ingestible device until it is determined that theingestible device is within the small intestine, and then the ingestibledevice may activate the gas-generating cell to generate gas and thuspropel a dispensable substance out of the housing. It is to be notedthat in at least some implementations, the electronic component isconfigured to automatically activate the gas-generating cell in responseto an identification of the location of the ingestible device, e.g.,based on analyzing the obtained reflectance as discussed above. Noexternal triggering outside the ingestible device is needed.Alternatively, the electronic component is not pre-programmed with anyactivation condition, such as but not limited to activation after apre-determined period, and/or the like. In at least anotherimplementation, the ingestible device does not rely on a pH-sensitiveenteric coating to determine the location, e.g., especially in specificparts of the GI tract where it is difficult to target based solely onpH-sensitive enteric coating, such as but not limited to sectionsimmediately after passing through the pyloric sphincter, or sectionsimmediately prior to the ileocecal valve. Further discussion oflocalization of the ingestible device may be found in PCT InternationalApplication No. PCT/US2015/052500, filed on Sep. 25, 2015, which isherein expressly incorporated by reference.

The memory unit can be provided with a memory storage component, such asa flash storage, EEPROM, and the like. The memory unit can be used tostore the instructions received from the base station and to storevarious other operational data, such as transit data and sensor datacollected by the optical sensing unit. For example, the memory unit canstore pre-defined reflectance parameters that indicates a specificlocation and instructions to identify an instant location of theingestible device based on a measured reflectance. For another example,the memory unit can store pre-defined parameters and instructions for anamount of the dispensable substance to be delivered, and when there aremultiple chambers for different dispensable substances, instructions todetermine and to dispense a dispensable substance based on the obtainedreflectance. In some embodiments, the microcontroller can operate toexecute the instructions stored at the memory unit, which may involveoperating other components of the ingestible device, such as the opticalsensing unit, the communication unit and the power supply.

In some embodiments, the power supply can include one or more batteries131 formed from different chemical compositions, such as lithiumpolymer, lithium carbon, silver oxide, alkaline, and the like. This canbe helpful in accommodating the different power requirements of thevarious components in the ingestible device. In some embodiments, thepower supply may include a silver oxide battery cell for supplying powerto the various components in the ingestible device. The battery cells131 that supply power to the power supply may operate at 1.55 V. Forexample, a silver oxide coin cell type battery, such as thosemanufactured by Renata™, may be used since the silver oxide coin cellbattery has discharge characteristics that suit the operation of theingestible device. In some embodiments, other types of battery cells maybe used.

In some embodiments, it is possible to include one or more battery cells131. For example, multiple coin cells may be used to provide highervoltage for the operation of the ingestible device. It may also bepossible for the power supply 131 to include one or more different typesof battery cells.

Also, the power supply may be split into one or more cell groups toprevent a temporary interruption or change at the power supply fromaffecting the overall operation of the ingestible device. For example,an example power supply can include three cells and each cell isoperable to provide 1.55 volts. In one example embodiment, the threecells can be provided as one cell group operable to provide 4.65 voltsas the full voltage. A voltage regulator may control the voltage that isprovided by the cell group. The voltage regulator may operate to providea regulated voltage, such as 3.3 volts, to the microcontroller, whileoperating to provide the full voltage to the optical sensing unit. Inanother example embodiment, the three cells can be provided as twodifferent cell groups, with a first cell group including two cells and asecond cell group including one cell. The first cell group, therefore,can provide 3.1 volts while the second cell group can be provide 1.55volts. The first cell group may be operable to provide 3.1 volts to themicrocontroller to prevent voltage variations. The first cell group andthe second cell group can then be combined to provide 4.65 volts to theoptical sensing unit.

In some embodiments, the power supply 131 may be removed from theingestible device to be recharged by recharging circuitry that isexternal to the ingestible device. In some embodiments, the power supply131 may be recharged while in the ingestible device when rechargingcircuitry is included on the PCB 132; for example, by providingcircuitry that allows the ingestible device to be inductively coupled toa base station and charged wirelessly.

In some embodiments, an ingestible device has a drive mechanism thatprovides positive pressure to provide sufficient energy to deliver abolus of dispensable substance (e.g., therapeutic agent) to a desiredlocation, such as the side wall of the small intestine, by way of a highvelocity jet through a nozzle. Exemplary alternative applications forthe drive mechanisms include providing energy to release mechanisms, andproviding suction to attach devices to the intestinal wall.

FIG. 45 illustrates an ingestible device 4500 including apre-pressurized actuator chamber 4503 and a sliding piston 4504,according to some embodiments described herein.

Ingestible device 4500 includes a device housing 4501. The devicehousing 4501 is composed of a cap portion 4502 a and a base portion 4502b in the illustrated embodiments. Ingestible device 4500 also includes apre-pressurized actuator chamber 4503 that is pressurized to a targetpressure, for example during manufacture or via air fill port 4506 priorto ingestion. The capsule incorporates an active release mechanism thatactivates as the capsule reaches the target location. As the releasemechanism activates, sliding piston 4504 will rapidly move to the left,pushing a high pressure jet of dispensable substance (e.g., therapeuticagent) through the nozzle.

Depending on the material used to form the walls of the device housing4501, the material could diffuse the compressed gas in thepre-pressurized actuator chamber 4503 over time, decreasing the internalpressure. To ensure that pressure is maintained in the ingestible device4500 over a period between fabrication and patient use, packaging couldbe pressurized to equal the internal pressure of the pill in certainembodiments; therefore, preventing the permeation of compressed gas fromthe ingestible device 4500. Assuming the gas expansion within thecapsule occurs very fast and an adiabatic polytropic process takesplace, gas laws are used to correlate the initial and final pressure ofthe gas with its volume change ratio.

For a polytropic process

pv^(k) = CTE

$\frac{p_{1}}{p_{2}} = \frac{v_{2}{}^{k}}{v_{1}{}^{k}}$

where p is the pressure, v is gas volume and k is the specific heatratio of the gas (1.4 for air).

The delivery pressure profile for a range of initial pressure and volumechange ratios are presented in Table 1. It can be observed that withincreasing the volume ratio of the compressed gas in the pre-pressurizedactuator chamber 4503, the variations in the delivery pressure becomessmaller. However, increasing the volume ratio will be at the cost ofreduced dispensable substance (e.g., therapeutic agent) volume. Acompromise between the two parameters can be made to arrive at adesirable pressure profile with adequate dispensable substance (e.g.,therapeutic agent) volume. Table 1 below provides sample results ofimplementation of pressurized gas for dispensable substance (e.g.,therapeutic agent) delivery embodiments disclosed herein.

TABLE 1 Gas initial pressure (psi) Gas volume change ratio* Estimatedvolume of the therapeutic agent chamber (ul)** Delivery pressure start-end (psi) 250 ⅔ 333 250-141 ½ 500 250-94 ⅓ 666 250-53 ¼ 750 250-35 200 ⅔333 200-113 ½ 500 200-75 ⅓ 666 200-42 ¼ 750 200-28 150 ⅔ 333 150-85 ½500 150-56 ⅓ 666 150-32 ¼ 750 150-21 100 ⅔ 333 100-56 ½ 500 100-37 ⅓ 666100-21 ¼ 750 100-14 * Represents the ratio of the initial to finalvolume of the gas before and after drug delivery. ** Assumes the totalavailable volume within the capsule for both gas and the drug is 1000ul.

In certain embodiments, the ingestible device 4500 is filled with aliquid dispensable substance (e.g., liquid therapeutic agent) inreservoir 4505. The liquid dispensable substance is ejected fromreservoir 4505 via piston 4504 sliding in reservoir 4505 in response toactuation by pressurized gas in the pre-pressurized actuator chamber4503 equilibrating. The pressurized gas in the pre-pressurized gaschamber 4503 is initially maintained in a pressurized state via anocclusion component, such as plug 4508, preventing the ejection of thedispensable substance from reservoir 4505. For example, the device 4500is placed in an external pressure chamber and chamber 4503 within theingestible device 4500 is elevated to a target pressure. Air fill port4506 is sealed (with adhesive or similar) in pressure chamber 4503 andplug 4508 is installed in conduit 4509. When plug 4508 is removed, forexample by being dissolved based on a reaction occurring at or near thetarget site the pressure in chamber 4503 is lowered as the chamber 4503volume increases as the piston 4504 moves further into reservoir 4505 asthe dispensable substance is evacuated from reservoir 4505 via exitconduit 4509.

In certain embodiments, the pressure in chamber 4503 is generated withinthe chamber itself via the release of gases during chemical reactionswithin the chamber. The chemical reaction between acids and bases isconsidered as a fast reaction, which can produce large amounts of gas asa product. The accumulation of product gas within the small capsule mayprovide the required pressure for a dispensable substance (e.g.,therapeutic agent) delivery jet. The amount of gas and pressure can becontrolled by careful selection of the reaction and the stoichiometry ofthe process. An ideal chemical reaction has to be fast and should notrelease toxic or unsafe products for in-vivo use. In particularembodiments, acetic acid and sodium bicarbonate are employed for thechemical reaction. All the reactants and products are considered to beingestible in small quantities. The products include carbonic acid andsodium acetate. In a low-pressure aquatic environment, Carbonic acidwill decompose into water and carbon dioxide in gaseous form. With therelease of carbon dioxide in a small container, the pressure within thechamber 4503 will rise providing the force needed for pushing piston4504 through reservoir 4505 towards the exit conduit 4509 to eject thedispensable substance therefrom.

In some embodiments, a burst disc may enable the release of drug bypurposefully fracturing at a targeted pressure. This approach iscommonly utilized in industrial applications as a safety mechanism inpressurized systems.

FIG. 46A illustrates a burst disc 4608 with an in line nozzle 4509. FIG.46B illustrates a partial sectional view of a burst disc holder 4610,according to some embodiments described herein. A burst disc 4608 mayenable the release of a dispensable substance, such as, for example, atherapeutic agent (for example from reservoir 4505) by purposefullyfracturing at a targeted pressure allowing the dispensable substance toexit a nozzle 4509 to a target location within the GI tract. A burstdisc 4608 can be used as the sole occlusion component in certainembodiments and can be used to provide isolation between upstreamcontamination and the dispensable substance payload in embodimentsincluding another occlusion component. The burst disc 4608 can be heldin place via clamped outer rings 4611 of disc holder 4610 asdemonstrated in FIG. 46B.

In certain embodiments, a custom built burst disc may be used.Advantages to this approach can include one or more of the following:reduced cost; increased control over the design and sizing;customization of design for operational and burst pressure properties;increased options for material type; and quality and tolerance control.Assuming for the sake of discussion that the burst disc is designed inthe form of a portion of a thin walled spherical pressure vessel(concave inside-convex outside), as shown in FIG. 46B, an analyticalapproach can be taken as follows. In this approach the shear and tensilestresses on the thin walled pressure vessel are estimated. Mohr circletheorem is used to estimate the principal stresses including tensile andshear stresses. For a thin walled spherical sphere the principalstresses on the outer wall are given by:

$\sigma_{1} = \sigma_{2} = \frac{pr}{2t}$

$\tau_{\max} = \frac{pr}{4t}$

where p is the pressure on the inner surface, r is the radius of thesphere that the burst disc is cut from and t is the thickness of thevessel.

The maximum shear stress on the inner wall of the vessel is given by:

$\tau_{\max} = \frac{1}{2}\left( {\sigma_{1} + p} \right) = \frac{pr}{2t}\left( {1 + \frac{t}{r}} \right)$

As described by the equations, the maximum stresses on the burst discare a function of pressure, diameter, and thickness of the wall. Theimpacts of stress concentrations on the perimeter of the disc is notconsidered in this approach. In order for a burst disc to operateproperly through the envisioned operating pressures, the principalstresses (normal and shear stresses) on the inner and outer surface ofthe vessel are desirably smaller than the maximum allowable stress. Themaximum allowable stresses are often the ultimate tensile and shearstresses of the material.

Another factor that can affect the performance of a burst disc is theelongation of material just before rupture. Plastic deformation andelongation of a material before rupture, results in changes in theequivalent diameter of the sphere under stress. This can result in adelay in rupture. It can be desirable to select material with minimalplastic elongation before the rupture. The design limitations, materialavailability from the supplier, and the product thickness and tolerancesmake the process of burst disc design a complicated process. A dynamicmodel was developed. The model receives the design properties as theinputs, subsequently calculating the minimum thickness of the materialrequired. Beyond this, it also investigates the impacts of thicknesstolerance and estimates a pressure range for the rupture of thematerial. This model compares the maximum principal stress of the systemwith the maximum tensile and shear stress of each material. Table 2lists results for 11 different shim materials from a supplier. Thedefinition for operating pressure in Table 2 is a nominal pressure fordesign and does not impact conveyed results, whereas minimum and maximumpressures are anticipated pressures for rupture. This analysis does notconsider variations to the tensile strength of the base material, whichcould add further spread for minimum and maximum pressures.

TABLE 2 A|1100-H14 Stainless Steel- AISI302 Steel-AISI1010Steel-AISI1095 Material No. 1 2 3 4 Foil thickness (inch) 0.011000.00200 0.00250 0.00100 Foil tolerance (inch) 0.00005 0.00005 0.000100.00010 Operating pressure (psi) 200 200 200 200 Rupture pressure-Min(psi) 300 410 210 210 Rupture pressure-Max (psi) 300 410 220 270Elongation at rupture (%per 2 inch) 9 12 20 9 A|1145-foil A|1235-foilBrass110-soft- annealed Ni200-annealed Material No. 5 6 7 8 Foilthickness (inch) 0.00700 0.01600 0.00700 0.00100 Foil tolerance (inch)0.00005 0.00005 0.00010 0.00005 Operating pressure (psi) 200 200 200 200Rupture pressure-Min (psi) 300 300 300 230 Rupture pressure-Max (psi)300 300 300 240 Elongation at rupture (%per 2 inch) 3 2 20 17 TitaniumBrass260-hard Bronze 510 Material No. 9 10 11 Foil thickness (inch)0.00500 0.00250 0.00550 Foil tolerance (inch) 0.00050 0.00010 0.00055Operating pressure (psi) 200 200 200 Rupture pressure-Min (psi) 230 300750 Rupture pressure-Max (psi) 290 300 900 Elongation at rupture (%per 2inch) 54 14 7

From the analysis, a number of off the shelf available materials couldbe considered suitable for use. Selection may depend upon relevantpressures, material properties, and material compatibility todispensable substance (e.g., therapeutic agent). In some embodiments, itmay be desirable to use materials with similar properties as Material #3and #4 with which chemical resistance and biocompatibility can besimulated and used. In certain embodiments, it may be desirable to usestainless steel 316L.

In some embodiments, one or more enteric coatings may be used as atrigger mechanism. FIG. 47 illustrates a portion of an ingestible device4700 including an enteric coating occlusion component 4708, according tosome embodiments described herein. As a cost-effective method to detectgeneral entry into the small intestine, enteric coatings are used inparticular embodiments as the occlusion component or as at least aportion of the occlusion component that is reconfigured based on changesin the regional pH levels. Accordingly, the pH level provides aneffective location detection signal for reconfiguring the occlusioncomponent and activating or releasing the dispensable substanceactuator. In certain embodiments, pressure acts on the underside of theenteric coating 4708, and as the coating 4708 is weakened due toexposure to the small intestinal luminal fluid, it fails, allowing therelease of a dispensable substance from the reservoir 4505.Complimentary coatings for sealing or strength (e.g. wax) may beincorporated on the interior or exterior surface of the enteric coatingto provide isolation of the dispensable substance (e.g., therapeuticagent) from the enteric coating (which may dissolve the coating), or toadd structural support. In some embodiments, an advantage ofincorporating the enteric coating on a tapering geometry of conduit 4509is that any pressure provided on the interior surface further compressesthe coating.

FIG. 48 shows stacked layers of an enteric coating 4708 for aningestible device, according to some embodiments described herein. As analternative to direct actuation with enteric coatings, concepts aredisclosed that utilize a coating to expose a secondary feature thatcause jet release. Some of these mechanisms rely on the exposure of anosmogen layer 4708 d to drive fluid. FIG. 48 , shows an implementationof an enteric coating 4708 a exposing a membrane 4708 c and osmogen 4708d via mesh layer 4708 b, which would drive the flow of water into thecapsule.

FIG. 49 illustrates an ingestible device 4900 including a magneticocclusion component 4908 b, a burst disc 4608, and a pre-pressurizedactuator chamber 4903, according to some embodiments described herein.FIG. 50 illustrates an ingestible device 5000 including a magneticocclusion component, a pre-pressurized actuator chamber 4903 and abioabsorbable plug 5008, according to some embodiments described herein.A magnetic stack (as shown FIG. 49 and FIG. 50 ), which upon peristalticor osmotic pressure application releases pneumatic pressure, allowingfor the delivery of a jet of dispensable substance through a conduit4509. As shown by FIG. 49 and FIG. 50 , osmotic pressure may be used toreconfigure the occlusion component that includes magnets 4908 a and4908 b in FIGS. 49 and 50 . The enteric coating 4908 c dissolves whenexposed to luminal fluid, exposing the membrane 4908 d and osmogen 4908e. The membrane 4908 d and osmogen 4908 e facilitate the movement ofliquid to create osmotic pressure on the magnet 4908 a. As the osmoticpressure builds up, magnet 4908 a will be pushed up in proximity tomagnet 4908 b. Magnet 4908 b will be pulled down providing a flowthrough path for a gas from pressurized chamber 4905 to interact withthe reservoir 4905 via connecting conduit 4911. The advantage of thissystem is that the mechanism may be completely sealed from the exteriorof the capsule, allowing for pressure to only project into the chamber4905. Note that an enteric coating/membrane stack 4908 c, 4908 d couldbe replaced by a method of leveraging peristalsis for pushing magnet4908 a. FIG. 49 is implemented with a burst disc 4608 as thesealing/release mechanism once the chamber 4905 is exposed to thepressurized chamber 4903. FIG. 50 is implemented with a bioabsorbableplug 5008 (e.g. enteric coating) that is dissolved and expelled once thereservoir 4905 is exposed to the pressurized actuator chamber 4903.

FIG. 51 illustrates an ingestible device 5100 including enteric slidingocclusion component 5102, a pre-pressurized actuator chamber 4903 and asliding component 5108, according to some embodiments described herein.An osmotic drive 4908, including an enteric coating 5102 andsemipermeable membrane 5104, is configured to move a sliding component5108. The sliding component 5108, once pushed by the osmotic drive 4908,will allow a flow-through port 4911 to connect the pressurized actuatorchamber 4903 to the reservoir 4905, providing dispensable substancedelivery through the nozzle 5108.

FIG. 52 illustrates an ingestible device 5200 including dissolvable pinocclusion component, a drug chamber 5202, a pre-pressurized chamber 5204and a sliding piston 5206, according to some embodiments describedherein. In another embodiment, an enteric coating 5208 b is dissolved,exposing a structural pin 5208 a (such as a glucose spike or hydrogel)that dissolves in the presence of intestinal luminal fluid. With thisdesign, as long as the pin 5208 a is in place, the force exerted on thepiston 5206 and the drug chamber 5202 is not large enough for the burstdisk 4608 to rupture. The enteric coating 5208 b and pin 5208 a willdissolve as the capsule 5200 is ingested and as a result, the pressureforce on the piston 5206 will increase. The full force of thepre-pressurized chamber 5204 translated onto the drug chamber 5202 viathe piston 5206 is large enough to rupture the burst disk 4608. Therupture of the burst disk 4608 results in a pressurized jet of liquidbeing delivered from the drug chamber 5202 through the nozzle 4509.

FIG. 53 illustrates an ingestible device 5300 including wax plug 5308 awith wire lead activators 5308 b, according to some embodimentsdescribed herein. In this method, the dispensing site is identifiedbased on collected reflected light. The reflectance of light in greenand red spectrums (with iterations to this methodology and algorithmactively being pursued) are measured and an algorithm is used tocorrelate the measured reflectance with the location in theGastrointestinal (GI) tract. This method provides a non-pH based systemto determine the anatomical locations of the capsule during fastedtransit. As the capsule 5300 reaches the target location, a signal isgenerated which will be used to activate an alternative releasemechanism.

With the inclusion of a printed circuit board assembly (herein referredto as PCBA) with light-based localization technologies, a meltingwax-based approach is presented. This functions by receiving anelectronic signal from an algorithmically defined detection point andproviding energy to a resistive heating element. This heating elementcauses a phase transition from solid to liquid, releasing the pressureand driving the jet of dispensable substance into the intestinal wall.One of the limiting factors to this approach is the additional costassociated with the PCBA.

Various embodiments disclosed herein use a nozzle, such as nozzle 4509,to create a high-pressure jet of fluid able to penetrate the intestinalwall. The nozzle can be directly connected to the dispensable substancereservoir (except, for example, when burst disc is used) and as a resultthe dispensable substance may dispense inadvertently if the opening ofthe nozzle is not sealed off. One approach to mitigate this includesusing a bioabsorbable material to close off the opening of the nozzle. Abioabsorbable plug refers to a plug made out of material that can beabsorbed by the body if injected into the intestinal wall or luminalregion. If the plug is in direct contact with the dispensable substance,a small sealant layer can be used to separate the plug from thedispensable substance to avoid unwanted dissolution. Particularembodiments use a passive bioabsorbable plug that only operates as asealing mechanism to close of the nozzle. A passive bioabsorbable plugmay be used to seal off the dispensable substance chamber and avoid anyunwanted spill of the dispensable substance. In this case, the internalpressure of the dispensable substance chamber is low and anothermechanism is used to activate the release of the dispensable substance.As the capsule reaches the target location, the pressure within thedispensable substance chamber rises up to a predefined value. This canbe done through use of any of the above-discussed release mechanisms.With the activation of the release mechanism, high-pressure fluid willovercome the adhesion of the bioabsorbable plug to the nozzle wall andwill push the plug out with a jet of fluid. In this case, the plug doesnot play a significant role in activation and release of the dispensablesubstance. After being shut out of the nozzle, the plug might fallwithin the GI tract or be injected into the intestinal wall. In bothcases after a certain period, it will be absorbed into the body.

Certain embodiments implement an active plug that acts both as thesealing mechanism and reconfigurable occlusion component for releasingthe actuator mechanism. An active bioabsorbable plug acts as both therelease mechanism and the sealing mechanism on the dispensable substancechamber. In this case, the plug is used to close off the opening of thenozzle. The dispensable substance chamber is already pressurized and, asa result, the plug is under pressure. The external body of the plugmight be in contact with the GI fluid or be covered with an entericcoating. As the capsule transits through the GI tract, the plug willstart dissolving (in case of enteric covered plug, the cover willdissolve before the plug starts dissolving). With time, the structuralintegrity of the plug will weaken as parts of the plug dissolves. Aftera predefined amount of time, the structure of the plug will weaken andwill not be able to hold of the high-pressure liquid any longer. At thispoint, the plug will shear off from the opening of the nozzle and willbe pushed out with the flow of high-pressure dispensable substance. Inthis case, the plug acts both as the sealing and release mechanism andas a result the term “active” is used.

FIG. 54 illustrates an ingestible device 5400 including apre-pressurized chamber 5403 and a bellows 5404, according to someembodiments described herein. Ingestible device 5400 includes twochambers: pressure actuator chamber 5403 and reservoir 5405 (FIG. 11 ).These two chambers are separated by the bellows 5404. The pressurechamber 5403 is filled with high-pressure gas and provides the drivemechanism needed to push the dispensable substance out of the nozzle5411. An adhesive layer 5412 is located on the housing opposite thenozzle 5411. The occlusion component or release mechanism for thisconcept consists of a bioabsorbable plug 5408 a (enteric coatings,glucose based with other matrices and combinations possible, see section5.5) separated from the liquid dispensable substance by a protectantlayer 5408 b. The plug 5408 a is configured to withstand the pressureforce exerted by the gas in pressurized actuator chamber 5403. The forceneeded to keep the plug 5408 a in place is a function of cross sectionarea where the plug 5408 a is installed. Because in this embodiment,plug is 5408 a placed at the small cross section area of the nozzleoutlet 5411, the force exerted on the plug 5408 a is relatively small.As the capsule 5400 is digested and moves through GI tract, thebioabsorbable plug 5408 a will start dissolving (see section 5.5). Aftercertain amount of time (which can be controlled by the properties of thebioabsorbable plug), the plug 5408 a will weaken or fully dissolve in GIfluid. After the plug 5408 a dissolves, the protectant layer 5408 b willbe ejected and the dispensable substance (e.g., in the form of a jet)will hit desired tissue, such as the internal wall of the targetlocation (e.g., the internal wall of the small intestine).

In some embodiments, an alternative to a pre-pressurized gas chamber isto use a spring mechanism to provide the required pressure for the jetdelivery mechanism. In certain embodiments, it may desirable to satisfyone or more of the following:

-   · Outer diameter of the spring smaller than inner diameter of the    capsule.-   · Compressed length of the spring minimized to leave more space for    drug.-   · Free length of the spring maximized and larger than free length of    inner cavity of the capsule to ensure an acceptable driving pressure    is provided throughout the entire time step of jet delivery.-   · Spring rate should be large enough to provide acceptable pressure    from the beginning until the end of drug delivery.-   · Initial pressure provided by the spring should be in the range of    100 to 250 PSI and the final pressure should not fall below 50 psi.

Based on the above factors, different springs from various suppliers maybe considered. Sample results of spring analysis/selection are presentedin Table 3. Optionally, a custom spring may be implemented. The use ofconical springs could also be implemented, potentially with a reductionin the solid length of the spring. In some embodiments, a piston may beimplemented with a spring such that piston could drive the fluid fromthe chamber. In certain embodiments, the piston could have one or moresealed interfaces.

TABLE 3 OD (in) Free length (in) Solid length (in) Rate (lbs/in)Delivery pressure start-end (psi) Item number — supplier 0.301 1.150.663 45 150-110 CDA-1115-0450-S, stocksprings.drtempleman.com 0.42 10.504 72 250-100 CEC-1000-0721-S stocksprings.drtempleman.com 0.234 0.880.34 92 235-50 PC040-234-7.500-MW-0.880-C-N-IN www.thespringstore.com0.36 0.8 0.46 94 190-10 PC059-360-7.750-SST-0.810-CG-N-INwww.thespringstore.com

FIG. 55 illustrates an ingestible 5500 device including a springactuator 5503 and a sliding piston 5504, according to some embodimentsdescribed herein. Ingestible device 5500 uses the potential energystored in a spring 5503 when compressed as the driving or actuatingmechanism for jet delivery of the dispensable substance. The occlusioncomponent or release mechanism consists of bioabsorbable plug 5508 aseparated from the reservoir 5505 by a protectant layer 5508 b. In thisembodiment, the inner volume of the capsule 5500 is divided into twosections separated by a sliding piston 5504. The left section (e.g.,reservoir 5505) is filled with dispensable substance and a spring 5503is mounted in the right section. The piston 5504 can freely move to theright or left depending on the net force exerted on the piston 5504(FIG. 55 ). An O-ring 5510 is used to provide the sealing requiredbetween the two sections, with alternative sealing means possible.Compressed spring 5503 applies a force on the piston 5504 and the piston5504 transfers this force to the liquid dispensable substance in form ofpressure. The same pressure will be transferred to the plug 5508 asealing the nozzle 5512. However, this pressure acts on a small area(area of the plug 5508 a). Therefore, the large force exerted by thespring 5503 translates into a small force on the sealing plug 5508 a. Asthe capsule 5500 is digested, it moves through GI tract and thebioabsorbable sealing plug 5508 a will start dissolving. After certainamount of time, the plug will weaken or fully dissolve in GI fluid. Assoon as the plug 5508 a weakens to the design threshold, the pressureinside the reservoir 5503 drops, the spring 5503 will expand deliveringdispensable substance (e.g., in the form of a high-pressure jet offluid) through the opening.

FIG. 56 illustrates an ingestible device 5600 including a springactuated slidable housing portion 5602 b, according to some embodimentsdescribed herein. Ingestible device 5600 consists of a pressurizedactuator 5603 chamber, a reservoir 5605 separated from the pressureactuator chamber 5603 by a deformable body 5604 such as bellows and aspring/enteric coating release mechanism The spring 5608 a is mounted onthe polycarbonate cap 5602 a from one end and to a sliding cap 5602 b onthe other end (FIG. 56 ). The stainless steel top slider 5602 b canslide to the left and right opening and closing the nozzle 5611. Anenteric ring 5608 b is used to keep the top slider closed. An O-ring anda bioabsorbable plug 5609 are used to provide the required sealing. Anadhesive seal 5612 is located on the housing, on the opposite end of thecapsule 5600 from the spring 5608 a. Compressed gas applies a force onthe bellows 5604 and the bellows 5604 transfer this force to the liquiddispensable substance in form of pressure. The same pressure will betransferred to the slider 5602 b in form of a radial force. However,this pressure acts on a small area (area of the exit orifice 5607).Therefore, the transverse load on the slider 5602 b is relatively small.When the capsule 5600 is assembled, the spring 5608 a is compressed(slider 5602 b in closed mode), and the enteric coating 5608 b keeps theslider 5602 b in position. As the capsule 5600 is digested, it movesthrough GI tract. The enteric coating 5608 b will dissolve when thecapsule 5600 passes through the intestinal fluid. With the dissolutionof the enteric coating 5608 b, the spring 5608 a will push the slider5602 b back away from the capsule 5600 (open mode). As a result, theexit orifice 5607 becomes concentric with the nozzle 5611 and the jet offluid will be released.

FIG. 57 illustrates an ingestible device 5700 with another springactuated slidable housing portion 5712, according to some embodimentsdescribed herein. Ingestible device 5700 uses a compressed spring(spring 5703) as the drive mechanism and a compressed spring 5708 a(spring with sliding top cap 5712 as the release mechanism. A piston5704 separates the reservoir 5705 from the spring chamber and an entericcoating 5708 b is used to initiate the release mechanism. An O-ring 5710is used to provide sealing between the piston 5704 and cylinder.Compressed spring 5703 applies a force on the piston 5704 and the piston5704 transfers this force to the liquid dispensable substance in theform of pressure. The same pressure will be transferred to the top capslider 5712 in form of a radial force. However, this pressure acts on asmall area (area of the exit orifice 5714) resulting in a smalltransverse force on the top slider 5712. When the capsule 5700 isassembled, spring 5703 is left in compressed mode (slider 5712 in closedposition). As the capsule 5700 is digested, it moves through GI tract.The enteric coating 5708 b will dissolve when the capsule 5700 passesthrough the intestinal fluid. With the dissolution of the entericcoating 5708 b, the spring 5708 a will push the slider 5712 back awayfrom the capsule 5700 (open mode). As a result, the exit orifice 5714becomes concentric with the nozzle 5716 and the jet of fluid will bereleased.

FIG. 58 illustrates an ingestible device 5800 including a melt awayocclusion component 5808 a and a pressurized chamber 5803, according tosome embodiments described herein. Ingestible device 5800 consists oftwo chambers, one chamber is filled with dispensable substance and theother chamber is filled with pressurized gas. A wax valve 5808 aactuated by localization board 5822 is used as the occlusion component.A large section of the pressure chamber 5803 is occupied by the releasemechanism and the required batteries 5821. Wax valve wires 5808 b areconnected to the wax valve 5808 a and will melt the wax using anelectric current. The timing of this operation is controlled by thelocalization board 5822. In this embodiment, a fully controlled releasemechanism is used. As the capsule 5800 reaches target area, thelocalization kit will activate and direct a predetermined electriccurrent toward the wax valve 5808 a. A heating element will receive thiscurrent and will melt or weaken the wax valve 5808 a. With weakening orremoval of the wax from the nozzle 5810, gas pressure from thepressurized chamber 5803 will push the bellows 5804 resulting in apressurized jet of liquid dispensable substance exiting the nozzle 5810,thus delivering the dispensable substance.

FIG. 59 illustrates an ingestible device 5900 including a dissolvablepin occlusion component 5908 and a spring actuated sliding piston 5914,according to some embodiments described herein. One of the mainchallenges of designing an effective capsule is the sealing between thetwo chambers inside the capsule since there is a significant pressuredifference between the two chambers, the dispensable substance tends tomove from the dispensable substance chamber into the pressure or springchamber. Certain embodiments address this by reducing the pressuredifference between the two chambers during the shelf life and before jetdelivery. For example, ingestible device 5900 includes a compressedspring 5903 is retained using a dissolvable pin 5908. Additionally, anO-ring 5912 is used to provide sealing between the piston 5914 andhousing. With this design, as long as the pin 5908 is in place, there isno force exerted on the piston 5904 and the liquid in chamber 5906. Theforce exerted by the spring 5903 will result in shear stress on the pin5908. The pin 5908 will dissolve as the capsule 5900 is ingested and asa result, the spring force will translate into a pressurized jet ofliquid. An enteric coating on the ends of the pin 5908 could furtherenhance the specificity of the triggering location. During the shelflife and before ingestion of the capsule 5900, there is not asignificant amount of pressure acting on the dispensable substance andconsequently, sealing challenges are easier to address. With a 200-psidesign pressure, the pin would be expected to hold approximately 20 lbf,and would involve design consideration to the shear strength of thedissolvable pin. As the capsule 5900 passes through the GI tract, thepin 5908 will start dissolving. As the pin 5908 dissolves, there is nosupport for the piston 5904 to keep the piston 5904 in place. The forceof the spring 5903 will result in a significant pressure in the fluid.At a certain point the pin 5908 will fail and the piston 5904 will moveto the left releasing a high-pressure jet of fluid through the nozzle5910.

FIG. 60 illustrates an ingestible device 6000 including shuttle sliderocclusion component 6012 and a pressurized chamber 6010, according tosome embodiments described herein. Ingestible device 6000 includes twochambers separated by a wall 6002 made of polycarbonate. The rightchamber is an adhesive seal 6028 and a pressurized chamber 6010,pressurized with gas, and a bellows 6006 is installed in the leftchamber. There are no openings connecting the two chambers 6006, 6010.An osmotic release mechanism is used to connect the two chambers 6006,6010 through a sliding valve 6012. As shown in FIG. 60 , osmogen 6014 iscontained within a small container below the sliding valve 6012. Osmogen6014 is separated from the GI fluid by a water permeable membrane 6016covered with enteric coating 6018. On the top of the osmogen 6014, ashuttle slider 6012 is mounted. The slider 6012 has an opening 6020 inthe middle. The slider shuttle 6012 is sandwiched between two slabs ofpolycarbonate with a pressure through port 6022. When the slider shuttle6012 is in closed form, the holes on the polycarbonate slabs are notconcentric with the hole on the slider shuttle 6012. When the slidershuttle 6012 is in open mode, the holes of the slider and polycarbonateslabs surrounding it all will be concentric letting gas and pressureexchange between the two chambers 6006, 6010.

As the ingestible device 6000 reaches the target location in the smallintestine, the enteric coating 6018 separating the membrane 6016 fromthe GI fluid will dissolve. Water will start moving through the membrane6016 into the osmogene 6014. With time, the volume of water within theosmogene 6014 will increase building up the pressure on the slidingshuttle 6012. As the pressure reaches certain value, the shuttle 6012will slide up and its port will become concentric with the ports on thetwo-polycarbonate slab next to the slider. At this point, high-pressuregas will move to left chamber. This results in an increase in thepressure on the bellows 6006. As the pressure on the bellows 6006reaches certain value, the bioabsorbable plug 6024 will be ejected fromthe nozzle 6026 and a jet of dispensable substance will be delivered tothe target tissue.

FIG. 61 illustrates an ingestible device 6100 including a hydrogen cellactuator 6112 and a burst disc occlusion component 6106, according tosome embodiments described herein. Ingestible device 6100 employshydrogen cells 6103 as the dispensable substance actuator. The selectionof the dispensing site is determined algorithmically. The localizationalgorithm is used to control the time of activation of hydrogen cell6103. Bellows 6104 are used to separate the dispensable substance fromthe localization device and hydrogen cell 6103. A burst disc 6106 isused to ensure that the dispensable substance does not eject the nozzle6108 before its pressure reaches the design pressure. The capsule 6100may also include a retention disk 6114 proximate to the burst disk 6106.As the capsule 6100 reaches the target location in GI tract,localization kit will activate the hydrogen cell 6103. With activation,the cell will start releasing hydrogen into the small closed volume 6105inside the capsule 6100 and the pressure will increase as more and morehydrogen releases. The hydrogen cell 6103 is powered using a battery6110 and is controlled and/or actuated using a printed circuit boardassembly 6112. As the hydrogen pressure increases in the capsule 6100,the pressure on the bellows 6104 will rise as well, pushing thedispensable substance on the burst disc 6106. When the pressure of thedispensable substance reaches the rupture pressure of the burst disc6106, the disc 6106 will burst directing the high-pressure dispensablesubstance through the nozzle 6108 to the target tissue.

FIG. 62 illustrates another ingestible device 6200 including a hydrogencell actuator 6014 and a burst disc occlusion component 6206, accordingto some embodiments described herein. In these embodiments, the internalchamber of the ingestible device 6200 is divided into two sections. Theleft section 6202, which is enclosed by bellows 6204, contains liquiddispensable substance. A burst disc 6206 is used to stop the flow of thedispensable substance though the nozzle 6218 until the dispensablesubstance pressure reaches the design criteria. The left section 6202further includes a retention ring 6222. The drive mechanism is installedin the right chamber 6208. The drive mechanism is activated through abioabsorbable coating mechanism, which is mounted on the outer surface6210 of the capsule 6200. The main difference between FIGS. 61 and 62 isthe replacement of localization kit with bioabsorbable coatingmechanism. These results in reduced costs and increase in the volumeavailable for the dispensable substance bellows.

As the capsule 6200 is ingested, it will pass through the digestionsystem. When the capsule 6200 enters small intestine, the bioabsorbablecoating 6212 will dissolve in the intestinal fluid. The segmentedconductors 6214 are exposed to the intestinal fluid, which acts asliquid conductor to close the hydrogen release circuit 6216. The capsule6200 is activated and starts releasing hydrogen inside the right chamber6208 of the capsule 6200, which includes a pressurizable chamber 6220.With the capsule 6200 fully sealed, release of hydrogen results inpressure rise inside the capsule 6200. As the gas pressure increases,the pressure on the bellows 6204 will rise and consequently, thedispensable substance pressure inside the bellows 6204 will increase.When the dispensable substance pressure reaches the design threshold ofthe burst disc 6206, the disc 6206 will rupture and high-pressuredispensable substance will flow through the nozzle 6218 toward thetarget area.

As an alternative to incorporating a pressurized air chamber, a vacuummay be substituted for the purposes of attachment to the intestinalwall. Similar to positive pressure concept, the suction conceptincorporates an active release/localization mechanism which wouldactivate as the capsule reaches the target location. As the releasemechanism activates, the suction mechanism will provide the requireddrive to suck the tissue into the capsule (or attach the capsule to thetissue). Upon attachment, another drive mechanism (such as needle andosmotic pressure) may be used to inject the drug into the tissue. Onepotential advantage of this concept may be to deliver relatively largepayloads of dispensable substance directly to the desired location,e.g., tissue of the GI tract of a subject.

FIG. 63 illustrates an ingestible device 6300 including a vacuumactuator chamber 6308 and enteric coating occlusion components,according to some embodiments described herein. Certain embodimentsinclude a vacuum actuator. The vacuum actuator 6308 can be used toattach the ingestible device to the intestinal wall and/or draw thedispensable substance from the dispensable substance reservoir, forexample during attachment to the intestinal wall. In certainembodiments, the ingestible device provides suction of approximately 7.5psi vacuum (7.2 psi absolute pressure).

Similar to positive pressure embodiments, the suction actuator includesan active release/localization mechanism activated as the capsulereaches the target location in response to a detection signal, e.g., acoating configured to dissolve in response to chemical interactions withchemicals generally found in close proximity to the target location. Asthe release mechanism activates, the suction mechanism will provide therequired drive to suck the tissue into the capsule 6300 (or attach thecapsule to the tissue). Upon attachment, another drive mechanism (suchas needle and osmotic pressure) can be used to inject the dispensablesubstance into the tissue.

Ingestible device 6300 describes a dispensable substance deliverymechanism based on such suction and direct needle injection. Unlike someof the previous concepts where a high-pressure jet of fluid is used toinject the dispensable substance into the tissue, in this concept, thedirect penetration of needle 6306 into the tissue is the dispensablesubstance delivery mechanism. The capsule 6300 includes several chambersinside a steel body. These chambers are needle chamber 6310,pre-vacuumed chamber 6312 (on the left) and, dispensable substancebellows 6314, salt chamber 6316 (on the right). The needle chamber hasan opening on the top with grip spears pointing toward the inner volumeof the chamber. The sharp end of the needle 6306 is mounted in themiddle of sucker opening 6304. The other end of the needle 3606 sits inthe bellows 6314. The needle chamber 6310 has a port 6318 on the bottomconnecting it to the pre-vacuumed chamber 6312. This port 6318 is sealedwith short delay enteric coating. The pre-vacuumed chamber 6312 sits atthe bottom of the needle chamber 6310 and has two ports 6320, 6318. One6320 on the left of the chamber is used to create the vacuum pressureand the other connects it to the needle chamber. The vacuum port 6320 issealed with adhesive seal 6322 after the chamber 6312 is vacuumed to therequired pressure. The right hand section of the capsule consists of twochambers: dispensable substance chamber 6314 and salt chamber 6316. Onechamber 6314 is enclosed by the bellows 6324 and will hold the liquiddispensable substance. One end of the needle 3606 sits inside thechamber 6314 providing a low resistance path for the dispensablesubstance to flow through the needle 6306 toward the target. The bellows6324 is surrounded by the salt chamber 6316. This chamber 6316 has anopening 6326 to the surroundings through a semi-permeable membrane 6328.This membrane is covered with long delay enteric coating.

As the capsule 6300 is ingested, it will move through the GI tract. TheGI tract fluid will enter the needle chamber 6310 and will dissolve theshort delay enteric coating. With proper design of the capsule 6300, itcan be ensured that the coating will fully dissolve as the capsule 6300reaches the target area. With the dissolution of the short delaycoating, the port 6322 is exposed and the pre-vacuumed chamber 6312 willsuck the target tissue into the needle chamber 6310. The needle 6306will penetrate the tissue and the spears 6330 will keep the capsule 6300attached to the tissue. With time, the long delay enteric coating willalso dissolve exposing the port 6326 and the semi-permeable membrane6328 to the GI fluid. Due to the osmotic effect, fluid will transportinto the salt chamber 6316 through the membrane 6328 increasing thepressure of the salt chamber 6316 and the bellows 6324. As the pressureof the salt chamber 6316 increases, the dispensable substance will bepushed out of the bellows 6324 through the needle 6306 into the targettissue. With time, due to natural defense mechanism of the body, thespears’ 6330 grip to the tissue will weaken and the tissue will bereleased.

FIG. 64 illustrates a system 6400 that includes an ingestible device6410 and an attachable storage reservoir 6420. Ingestible device 6410can be designed as described elsewhere herein, except that it does notinclude a storage reservoir as an integral component. Attachablereservoir 6420 can be designed as described elsewhere herein, exceptthat it is not an integral component of ingestible device 6410.

In some embodiments, storage reservoir 6420 is loaded with a dispensablesubstance (e.g., therapeutic agent) prior to being positioned in and/orcoupled to ingestible device 6410. As shown in FIG. 64 , ingestibledevice housing 6410 includes one or more openings 6430 configured tohouse storage reservoir 6420. However, other embodiments can beimplemented for attaching an attachable storage reservoir to aningestible device, some of which are discussed below. Optionallyingestible device housing 6410 includes one or more openings configuredas a vent.

Typically, a dispensable substance is disposed in storage reservoir6410, and storage reservoir 6420 is subsequently attached to ingestibledevice 6410. For example, reservoir 6420 can be manufactured, packagedand/or shipped separately from device 6410. Optionally, reservoir 6420and device 6410 are combined relatively soon before a subject is toingest the device. Given that the safe life time for the ingestibledevice devoid of dispensable substance (e.g., therapeutic agent) islikely to be substantially longer than the safe life time of thedispensable substance (e.g., therapeutic agent), in some cases, using anattachable device can be desirable, particularly if it is consideredundesirable or inconvenient to load dispensable substance into aningestible device in which a storage reservoir is an integral component.

In general, an attachable storage reservoir and ingestible device can bedesigned in any appropriate fashion so that the storage reservoir canattach to the ingestible device when desired. Examples of designsinclude a storage reservoir that fits entirely within the ingestibledevice (e.g., in the ingestible device so that the storage reservoir issealed within the device at the time the device is ingested by asubject), a storage reservoir that fits partially within the ingestibledevice, and a storage reservoir that is carried by the housing of thedevice. In some embodiments, the storage reservoir snap fits with theingestible device. In certain embodiments, the storage reservoir isfriction fit with the ingestible device. Optionally, the storagereservoir is connected with the ingestible device via a threadedconnection. Such a threaded connection could include a seal, such as anO-ring seal. In some embodiments, the storage reservoir is held togetherwith the ingestible device via a biasing mechanism, such as one or moresprings, one or more latches, one or more hooks, one or more magnets,and/or electromagnetic radiation. In certain embodiments, the storagereservoir can be a pierceable member. In some embodiments, theingestible device has a sleeve into which the storage reservoir securelyfits. In some embodiments, the storage reservoir is disposed in/on aslidable track/groove so that it can move onto a piercing needle whendelivery of the dispensable substance is desired. In certain embodimentsa seal can be used in addition to the attachment mechanism to reduce oreven prevent ingress of fluid and/or to capture internal pressure withinthe capsule (e.g., for gas-generating cell embodiments and/orpre-pressurized embodiments). In certain embodiments, the storagereservoir is made of a soft plastic coating, which is contacted with aneedle at any orientation to deliver the dispensable substance whendesired. Generally, the storage reservoir can be made of one or moreappropriate materials, such as, for example, one or more plastics and/orone or more metals or alloys. Exemplary materials include silicone,polyvinyl chloride, polycarbonate and stainless steel. Optionally, thedesign may be such that the storage reservoir carries some or all of theelectrical componentry to be used by the ingestible device. Although theforegoing discussion relates to one storage reservoir, it is to beunderstood that an ingestible device can be designed to carry anydesired number (e.g., two, three, four, five) storage reservoirs.Different storage reservoirs can have the same or different designs. Insome embodiments, the ingestible device (when fully assembled andpackaged) satisfies the regulatory requirements for marketing a medicaldevice in one or more jurisdictions selected from the United States ofAmerica, the European Union or any member state thereof, Japan, China,Brazil, Canada, Mexico, Colombia, Argentina, Chile, Peru, Russia, theUK, Switzerland, Norway, Turkey, Israel, any member state of the GulfCooperative Council, South Africa, India, Australia, New Zealand, SouthKorea, Singapore, Thailand, the Philippines, Malaysia, Viet Nam, andIndonesia.

Although the foregoing description is with respect to system 6400including ingestible device 6410 and attachable reservoir 6420, thedisclosure is not limited in this sense. For example, in someembodiments, an ingestible device can contain one or more storagereservoirs as an integral component and also be designed for use withone or more attachable reservoirs. Optionally, attachable reservoir 6420can also include features to allow recognition of the reservoir for thepurposes of adjusting the dispensing parameters of the capsule and/orprevent the re-use of the device. Typically, the ingestible devicesdisclosed herein include one or more processing devices, and one moremachine readable hardware storage devices. In some embodiments, the oneor more machine readable hardware storage devices store instructionsthat are executable by the one or more processing devices to determinethe location of the ingestible device in a portion of a GI tract of thesubject. In certain embodiments, the one or more machine readablehardware storage devices store instructions that are executable by theone or more processing devices to transmit data to an external device(e.g., a base station external to the subject, such as a base stationcarried on an article worn by the subject) capable of implementing thedata to determine the location of the device within the GI tract of thesubject.

In some embodiments, the location of the ingestible device within the GItract of the subject can be determined to an accuracy of at least 85%,e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least99%, 100%. In such embodiments, the portion of the portion of the GItract of the subject can include, for example, the esophagus, thestomach, duodenum, the jejunum, and/or the terminal ileum, cecum andcolon.

In certain embodiments, the location of the ingestible device within theesophagus of the subject can be determined to an accuracy of at least85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, atleast 99%, 100%.

In some embodiments, the location of the ingestible device within thestomach of the subject can be determined to an accuracy of at least 85%,e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least99%, 100%.

In certain embodiments, the location of the ingestible device within theduodenum of the subject can be determined to an accuracy of at least85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, atleast 99%, 100%.

In some embodiments, the location of the ingestible device within thejejunum of the subject can be determined to an accuracy of at least 85%,e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least99%, 100%.

In certain embodiments, the location of the ingestible device within theterminal ileum, cecum and colon of the subject can be determined to anaccuracy of at least 85%, e.g., at least 90%, at least 95%, at least97%, at least 98%, at least 99%, 100%.

In some embodiments, the location of the ingestible device within thececum of the subject can be determined to an accuracy of at least 85%,e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least99%, 100%.

As used herein, the term “reflectance” refers to a value derived fromlight emitted by the device, reflected back to the device, and receivedby a detector in or on the device. For example, in some embodiments thisrefers to light emitted by the device, wherein a portion of the light isreflected by a surface external to the device, and the light is receivedby a detector located in or on the device.

As used herein, the term “illumination” refers to any electromagneticemission. In some embodiments, an illumination may be within the rangeof Infrared Light (IR), the visible spectrum and ultraviolet light (UV),and an illumination may have a majority of its power centered at aparticular wavelength in the range of 100 nm to 1000 nm. In someembodiments, it may be advantageous to use an illumination with amajority of its power limited to one of the infrared (750 nm-1000 nm),red (600 nm-750 nm), green (495 nm-600 nm), blue (400 nm-495 nm), orultraviolet (100 nm-400 nm) spectrums. In some embodiments a pluralityof illuminations with different wavelengths may be used. Forillustrative purposes, the embodiments described herein may refer to theuse of green or blue spectrums of light. However, it is understood thatthese embodiments may use any suitable light having a wavelength that issubstantially or approximately within the green or blue spectra definedabove, and the localization systems and methods described herein may useany suitable spectra of light.

Referring now to FIG. 65 , shown therein is a view of an exampleembodiment of an ingestible device 65100, which may be used to identifya location within a gastrointestinal (GI) tract. It is to be understoodthat certain details regarding the design of ingestible device 65100 arenot shown in FIG. 65 and the following figures, and that, in general,various aspect of ingestible devices described elsewhere herein can beimplemented in ingestible device 65100 and the ingestible devices shownin the following figures.

In some embodiments, ingestible device 65100 may be configured toautonomously determine whether it is located in the stomach, aparticular portion of the small intestine such as a duodenum, jejunum,or ileum, or the large intestine by utilizing sensors operating withdifferent wavelengths of light. Additionally, ingestible device 65100may be configured to autonomously determine whether it is located withincertain portions of the small intestine or large intestine, such as theduodenum, the jejunum, the cecum, or the colon.

Ingestible device 65100 may have a housing 65102 shaped similar to apill or capsule. The housing 65102 of ingestible device 65100 may have afirst end portion 65104, and a second end portion 65106. The first endportion 65104 may include a first wall portion 65108, and second endportion 65106 may include a second wall portion 65110. In someembodiments, first end portion 65104 and second end portion 65106 ofingestible device 65100 may be manufactured separately, and may beaffixed together by a connecting portion 65112.

In some embodiments, ingestible device 65100 may include an opticallytransparent window 65114. Optically transparent window 65114 may betransparent to various types of illumination in the visible spectrum,infrared spectrum, or ultraviolet light spectrum, and ingestible device65100 may have various sensors and illuminators located within thehousing 65102, and behind the transparent window 65114. This may allowingestible device 65100 to be configured to transmit illumination atdifferent wavelengths through transparent window 65114 to an environmentexternal to housing 65102 of ingestible device 65100, and to detect areflectance from a portion of the illumination that is reflected backthrough transparent window 65114 from the environment external tohousing 65102. Ingestible device 65100 may then use the detected levelof reflectance in order to determine a location of ingestible device65100 within a GI tract. In some embodiments, optically transparentwindow 65114 may be of any shape and size, and may wrap around thecircumference of ingestible device 65100. In this case, ingestibledevice 65100 may have multiple sets of sensors and illuminatorspositioned at different locations azimuthally behind window 65114.

In some embodiments, ingestible device 65100 may optionally include anopening 65116 in the second wall portion 65110. In some embodiments, thesecond wall portion 65110 may be configured to rotate around thelongitudinal axis of ingestible device 65100 (e.g., via a suitable motoror other actuator housed within ingestible device 65100). This may allowingestible device 65100 to obtain a fluid sample from the GI tract, orrelease a substance into the GI tract, through opening 65116.

FIG. 66 shows an exploded view of ingestible device 65100. In someembodiments, ingestible device 65100 may optionally include a rotationassembly 65118. Optional rotation assembly 65118 may include a motor65118-1 driven by a microcontroller (e.g., a microcontroller coupled toprinted circuit board 65120), a rotation position sensing ring 65118-2,and a storage sub-unit 65118-3 configured to fit snugly within thesecond end portion 65104. In some embodiments, rotation assembly 65118may cause second end portion 65104, and opening 65116, to rotaterelative to the storage sub-unit 65118-3. In some embodiments, there maybe cavities on the side of storage sub-unit 65118-3 that function asstorage chambers. When the opening 65116 is aligned with a cavity on theside of the storage sub-unit 65118-3, the cavity on the side of thestorage sub-unit 65118-3 may be exposed to the environment external tothe housing 65102 of ingestible device 65100. In some embodiments, thestorage sub-unit 65118-3 may be loaded with a medicament or othersubstance prior to the ingestible device 65100 being administered to asubject. In this case, the medicament or other substance may be releasedfrom the ingestible device 65100 by aligning opening 65116 with thecavity within storage sub-unit 65118-3. In some embodiments, the storagesub-unit 65118-3 may be configured to hold a fluid sample obtained fromthe GI tract. For example, ingestible device 65100 may be configured toalign opening 65116 with the cavity within storage sub-unit 65118-3,thus allowing a fluid sample from the GI tract to enter the cavitywithin storage sub-unit 65118-3. Afterwards, ingestible device 65100 maybe configured to seal the fluid sample within storage sub-unit 65118-3by further rotating the second end portion 65106 relative to storagesub-unit 65118-3. In some embodiments, storage sub-unit 118-3 may alsocontain a hydrophilic sponge, which may enable ingestible device 65100to better draw certain types of fluid samples into ingestible device65100. In some embodiments, ingestible device 65100 may be configured toeither obtain a sample from within the GI tract, or to release asubstance into the GI tract, in response to determining that ingestibledevice 65100 has reached a predetermined location within the GI tract.For example, ingestible device 65100 may be configured to obtain a fluidsample from the GI tract in response to determining that the ingestibledevice has entered the jejunum portion of the small intestine (e.g., asdetermined by process 65900 discussed in relation to FIG. 73 ). Otheringestible devices capable of obtaining samples or releasing substancesare discussed in commonly-assigned PCT Application No. PCT/CA2013/000133filed Feb. 15, 2013, commonly-assigned U.S. Provisional Application No.62/385,553, and commonly-assigned U.S. Provisional Application No.62/376,688, which each are hereby incorporated by reference herein intheir entirety. It is understood that any suitable method of obtainingsamples or releasing substances may be incorporated into some of theembodiments of the ingestible devices disclosed herein, and that thesystems and methods for determining a location of an ingestible devicemay be incorporated into any suitable type of ingestible device.

Ingestible device 65100 may include a printed circuit board (PCB) 65120,and a battery 65128 configured to power PCB 65120. PCB 65120 may includea programmable microcontroller, and control and memory circuitry forholding and executing firmware or software for coordinating theoperation of ingestible device 65100, and the various components ofingestible device 65100. For example, PCB 65120 may include memorycircuitry for storing data, such as data sets of measurements collectedby sensing sub-unit 65126, or instructions to be executed by controlcircuitry to implement a localization process, such as, for example, oneor more of the processes, discussed herein, including those discussedbelow in connection with one or more of the associated flow charts. PCB65120 may include a detector 65122 and an illuminator 65124, whichtogether form sensing sub-unit 65126. In some embodiments, controlcircuitry within PCB 65120 may include processing units, communicationcircuitry, or any other suitable type of circuitry for operatingingestible device 65100. For illustrative purposes, only a singledetector 65122 and a single illuminator 65124 forming a single sensingsub-unit 65 126 are shown. However, it is understood that in someembodiments there may be multiple sensing sub-units, each with aseparate illuminator and detector, within ingestible device 65100. Forexample, there may be several sensing sub-units spaced azimuthallyaround the circumference of the PCB 65120, which may enable ingestibledevice 65100 to transmit illumination and detect reflectances or ambientlight in all directions around the circumference of the device. In someembodiments, sensing sub-unit 65126 may be configured to generate anillumination using illuminator 65124, which is directed through thewindow 65114 in a radial direction away from ingestible device 65100.This illumination may reflect off of the environment external toingestible device 65100, and the reflected light coming back intoingestible device 65100 through window 65114 may be detected as areflectance by detector 65122.

In some embodiments, window 65114 may be of any suitable shape and size.For example, window 65114 may extend around a full circumference ofingestible device 65100. In some embodiments there may be a plurality ofsensing sub-units (e.g., similar to sensing sub-unit 65126) located atdifferent positions behind the window. For example, three sensingsub-units may be positioned behind the window at the same longitudinallocation, but spaced 120 degrees apart azimuthally. This may enableingestible device 65100 to transmit illuminations in all directionsradially around ingestible device 65100, and to measure each of thecorresponding reflectances.

In some embodiments, illuminator 65124 may be capable of producingillumination at a variety of different wavelengths in the ultraviolet,infrared, or visible spectrum. For example, illuminator 65124 may beimplemented by using Red-Green-Blue Light-Emitting diode packages(RGB-LED). These types of RGB-LED packages are able to transmit red,blue, or green illumination, or combinations of red, blue, or greenillumination. Similarly, detector 65122 may be configured to sensereflected light of the same wavelengths as the illumination produced byilluminator 65124. For example, if illuminator 65124 is configured toproduce red, blue, or green illumination, detector 65122 may beconfigured to detect different reflectances produced by red, blue, orgreen illumination (e.g., through the use of an appropriately configuredphotodiode). These detected reflectances may be stored by ingestibledevice 65100 (e.g., within memory circuitry of PCB 65120), and may thenbe used by ingestible device 65100 in determining a location ofingestible device 65100 within the GI tract (e.g., through the use ofprocess 65500 (FIG. 69 ), process 65600 (FIG. 70 ), or process 65900(FIG. 73 )).

It is understood that ingestible device 65100 is intended to beillustrative, and not limiting. It will be understood that modificationsto the general shape and structure of the various devices and mechanismsdescribed in relation to FIG. 65 and FIG. 66 may be made withoutsignificantly changing the functions and operations of the devices andmechanisms. For example, ingestible device 65100 may have a housingformed from a single piece of molded plastic, rather than being dividedinto a first end portion 65104 and a second end portion 65106. As analternate example, the location of window 65114 within ingestible device65100 may be moved to some other location, such as the center ofingestible device 65100, or to one of the ends of ingestible device65100. Moreover, the systems and methods discussed in relation to FIGS.65-74 may be implemented on any suitable type of ingestible device,provided that the ingestible device is capable of detecting reflectancesor levels of illumination in some capacity. For example, in someembodiments ingestible device 65100 may be modified to replace detector65122 with an image sensor, and the ingestible device may be configuredto measure relative levels of red, blue, or green light by decomposing arecorded image into its individual spectral components. Other examplesof ingestible devices with localization capabilities, which may beutilized in order to implement the systems and methods discussed inrelation to FIGS. 65-75 , are discussed in co-owned PCT Application No.PCT/US2015/052500 filed on Sep. 25, 2015, which is hereby incorporatedby reference herein in its entirety. Furthermore, it should be notedthat the features and limitations described in any one embodiment may beapplied to any other embodiment herein, and the descriptions andexamples relating to one embodiment may be combined with any otherembodiment in a suitable manner.

FIG. 67 is a diagram of an ingestible device during an example transitthrough a gastrointestinal (GI) tract, in accordance with someembodiments of the disclosure. Ingestible device 65300 may include anyportion of any other ingestible device discussed in this disclosure(e.g., ingestible device 65100 (FIG. 65 )), and may be any suitable typeof ingestible device with localization capabilities. For example,ingestible device 65300 may be one embodiment of ingestible device 65100without the optional opening 65116 (FIG. 65 ) or optional rotationassembly 65118 (FIG. 66 )). In some embodiments, ingestible device 65300may be ingested by a subject, and as ingestible device 65300 traversesthe GI tract, ingestible device 65300 may be configured to determine itslocation within the GI tract. For example, the movement of ingestibledevice 65300 and the amount of light detected by ingestible device 65300(e.g., via detector 65122 (FIG. 66 )) may vary substantially dependingon the location of ingestible device 65300 within the GI tract, andingestible device 65300 may be configured to use this information todetermine a location of ingestible device 65300 within the GI tract. Forinstance, ingestible device 65300 may detect ambient light from thesurrounding environment, or reflectances based on illumination generatedby ingestible device 65300 (e.g., generated by illuminator 65124 (FIG.65 )), and use this information to determine a location of ingestibledevice 65300 through processes, such as described herein. The currentlocation of ingestible device 65300, and the time that ingestible device65300 detected each transition between the various portions of the GItract, may then be stored by ingestible device 65300 (e.g., in memorycircuitry of PCB 65120 (FIG. 66 )), and may be used for any suitablepurpose.

Shortly after ingestible device 65300 is ingested, ingestible devicewill traverse the esophagus 65302, which may connect the subject’s mouthto a stomach 65306. In some embodiments, ingestible device 65300 may beconfigured to determine that it has entered the esophagus portion GItract by measuring the amount and type of light (e.g., via detector65122 (FIG. 66 )) in the environment surrounding the ingestible device65300. For instance, ingestible device 65300 may detect higher levels oflight in the visible spectrum (e.g., via detector 65122 (FIG. 66 ))while outside the subject’s body, as compared to the levels of lightdetected while within the GI tract. In some embodiments, ingestibledevice 65300 may have previously stored data (e.g., on memory circuitryof PCB 65120 (FIG. 66 )) indicating a typical level of light detectedwhen outside of the body, and the ingestible device 65300 may beconfigured to determine that entry to the body has occurred when adetected level of light (e.g., detected via detector 65122 (FIG. 66 ))has been reduced beyond a threshold level (e.g., at least a 20-30%reduction) for a sufficient period of time (e.g., 5.0 seconds).

In some embodiments, ingestible device 65300 may be configured to detecta transition from esophagus 65302 to stomach 65306 by passing throughsphincter 65304. In some embodiments, ingestible device 65300 may beconfigured to determine whether it has entered stomach 65306 based atleast in part on a plurality of parameters, such as but not limited tothe use of light or temperature measurements (e.g., via detector 65122(FIG. 66 ) or via a thermometer within ingestible device 65300), pHmeasurements (e.g., via a pH meter within ingestible device 65300), timemeasurements (e.g., as detected through the use of clock circuitryincluded within PCB 65120 (FIG. 66 )), or any other suitableinformation. For instance, ingestible device 65300 may be configured todetermine that ingestible device 65300 has entered stomach 65306 afterdetecting that a measured temperature of ingestible device 65300 exceeds31° C. Additionally or alternately, ingestible device 65300 may beconfigured to automatically determine it has entered stomach 65306 afterone minute (or another pre-set time duration parameter, 80 seconds, 90seconds, etc.) has elapsed from the time that ingestible device 65300was ingested, or one minute (or another pre-set time duration parameter,80 seconds, 90 seconds, etc.) from the time that ingestible device 65300detected that it has entered the GI tract.

Stomach 65306 is a relatively large, open, and cavernous organ, andtherefore ingestible device 65300 may have a relatively large range ofmotion. By comparison, the motion of ingestible device 65300 isrelatively restricted within the tube-like structure of the duodenum65310, the jejunum 65314, and the ileum (not shown), all of whichcollectively form the small intestine. Additionally, the interior ofstomach 65306 has distinct optical properties from duodenum 65310 andjejunum 65314, which may enable ingestible device 65300 to detect atransition from stomach 65306 to duodenum 65310 through the appropriateuse of measured reflectances (e.g., through the use of reflectancesmeasured by detector 65122 (FIG. 66 )), as used in conjunction withprocess 65600 (FIG. 70 )).

In some embodiments, ingestible device 65300 may be configured to detecta pyloric transition from stomach 65306 to duodenum 65310 through thepylorus 65308. For instance, in some embodiments, ingestible device65300 may be configured to periodically generate illumination in thegreen and blue wavelengths (e.g., via illuminator 65124 (FIG. 66 )), andmeasure the resulting reflectances (e.g., via detector 65122 (FIG. 66)). Ingestible device 65300 may be configured to then use a ratio of thedetected green reflectance to the detected blue reflectance to determinewhether ingestible device 65300 is located within the stomach 65306, orduodenum 65310 (e.g., via process 65600 (FIG. 70 )). In turn, this mayenable ingestible device 65300 to detect a pyloric transition fromstomach 65306 to duodenum 65310, an example of which is discussed inrelation to FIG. 70 .

Similarly, in some embodiments, ingestible device 65300 may beconfigured to detect a reverse pyloric transition from duodenum 65310 tostomach 65306. Ingestible device 65300 will typically transitionnaturally from stomach 65306 to duodenum 65310, and onward to jejunum65314 and the remainder of the GI tract. However, similar to otheringested substances, ingestible device 65300 may occasionally transitionfrom duodenum 65310 back to stomach 65306 as a result of motion of thesubject, or due to the natural behavior of the organs with the GI tract.To accommodate this possibility, ingestible device 65300 may beconfigured to continue to periodically generate illumination in thegreen and blue wavelengths (e.g., via illuminator 65124 (FIG. 66 )), andmeasure the resulting reflectances (e.g., via detector 65122 (FIG. 66 ))to detect whether or not ingestible device 65300 has returned to stomach65306. An exemplary detection process is described in additional detailin relation to FIG. 70 .

After entering duodenum 65310, ingestible device 65300 may be configuredto detect a transition to the jejunum 65314 through the duodenojejunalflexure 65312. For example, ingestible device 65300 may be configured touse reflectances to detect peristaltic waves within the jejunum 65314,caused by the contraction of the smooth muscle tissue lining the wallsof the jejunum 65314. In particular, ingestible device 65300 may beconfigured to begin periodically transmitting illumination (andmeasuring the resulting reflectances (e.g., via detector 65122 andilluminator 65124 of sensing sub-unit 65126 (FIG. 66 )) at asufficiently high frequency in order to detect muscle contractionswithin the jejunum 65314. Ingestible device 65300 may then determinethat it has entered the jejunum 65314 in response to having detectedeither a first muscle contraction, or a predetermined number of musclecontractions (e.g., after having detected three muscle contractions insequence). The interaction of ingestible device 65300 with the walls ofjejunum 65314 is also discussed in relation to FIG. 68 , and an exampleof this detection process is described in additional detail in relationto FIG. 73 .

FIG. 68 is a diagram of an ingestible device during an example transitthrough a jejunum, in accordance with some embodiments of thedisclosure. Diagrams 65410, 65420, 65430, and 65440 depict ingestibledevice 65400 as it traverses through a jejunum (e.g., jejunum 65314),and how ingestible device 65400 interacts with peristaltic waves formedby walls 65406A and 65406B (collectively, walls 65406) of the jejunum.In some implementations, ingestible device 65400 may include any portionof any other ingestible device discussed in this disclosure (e.g.,ingestible device 65100 (FIG. 65 ) or ingestible device 65300 (FIG. 67)), and may be any suitable type of ingestible device with localizationcapabilities. For example, ingestible device 65400 may be substantiallysimilar to the ingestible device 65300 (FIG. 67 ) or ingestible device65100 (FIG. 66 ), with window 65404 being the same as window 65114 (FIG.65 ), and sensing sub-unit 65402 being the same as sensing sub-unit65126 (FIG. 66 ).

Diagram 65410 depicts ingestible device 400 within the jejunum, when thewalls 65406 of the jejunum are relaxed. In some embodiments, theconfined tube-like structure of the jejunum naturally causes ingestibledevice 65400 to be oriented longitudinally along the length of thejejunum, with window 65404 facing walls 65406. In this orientation,ingestible device 65400 may use sensing sub-unit 65402 to generateillumination (e.g., via illuminator 65124 (FIG. 66 )) oriented towardswalls 65406, and to detect the resulting reflectances (e.g., viadetector 65122 (FIG. 66 )) from the portion of the illuminationreflected off of walls 65406 and back through window 65404. In someembodiments, ingestible device 65400 may be configured to use sensingsub-unit 65402 to generate illumination and measure the resultingreflectance with sufficient frequency to detect peristaltic waves withinthe jejunum. For instance, in a healthy human subject, peristaltic wavesmay occur at a rate of approximately 0.05 Hz to 0.33 Hz. Therefore, theingestible device 65400 may be configured to generate illumination andmeasure the resulting reflectance at least once every 2.5 seconds (i.e.,potentially minimum rate to detect a 0.2 Hz signal), and preferably at ahigher rate, such as once every 0.5 seconds, which may improve theoverall reliability of the detection process due to more data pointsbeing available. It is understood that the ingestible device 65400 neednot gather measurements at precise intervals, and in some embodimentsthe ingestible device 65400 may be adapted to analyze data gathered atmore irregular intervals, provided that there are still a sufficientnumber of appropriately spaced data points to detect 0.05 Hz to 0.33 Hzsignals.

Diagram 65420 depicts ingestible device 65400 within the jejunum, whenthe walls 65406 of the jejunum begin to contract and form a peristalticwave. Diagram 65420 depicts contracting portion 65408A of wall 65406Aand contracting portion 65408B of wall 65406B (collectively, contractingportion 65408 of wall 65406) that form a peristaltic wave within thejejunum. The peristaltic wave proceeds along the length of the jejunumas different portions of wall 65406 contract and relax, causing it toappear as if contracting portions 65408 of wall 65406 proceed along thelength of the jejunum (i.e., as depicted by contracting portions 65408proceeding from left to right in diagrams 65410-65430). While in thisposition, ingestible device 65400 may detect a similar level ofreflectance (e.g., through the use of illuminator 65124 and detector65122 of sensing sub-unit 65126 (FIG. 66 )) as detected when there is noperistaltic wave occurring (e.g., as detected when ingestible device65400 is in the position indicated in diagram 65410).

Diagram 65430 depicts ingestible device 65400 within the jejunum, whenthe walls 65406 of the jejunum continue to contract, squeezing aroundingestible device 65400. As the peristaltic wave proceeds along thelength of the jejunum, contracting portions 65408 of wall 65406 maysqueeze tightly around ingestible device 65400, bringing the innersurface of wall 65406 into contact with window 65404. While in thisposition, ingestible device 65400 may detect a change in a reflectancedetected as a result of illumination produced by sensing sub-unit 65402.The absolute value of the change in the measured reflectance may dependon several factors, such as the optical properties of the window 65404,the spectral components of the illumination, and the optical propertiesof the walls 65406. However, ingestible device 65400 may be configuredto store a data set with the reflectance values over time, and searchfor periodic changes in the data set consistent with the frequency ofthe peristaltic waves (e.g., by analyzing the data set in the frequencydomain, and searching for peaks between 0.05 Hz to 0.33 Hz). This mayenable ingestible device 65400 to detect muscle contractions due toperistaltic waves without foreknowledge of the exact changes inreflectance signal amplitude that may occur as a result of detecting themuscle contractions of the peristaltic wave. An example procedure fordetecting muscle contractions is discussed further in relation to FIG.73 , and an example of a reflectance data set gathered while ingestibledevice 65400 is located within the jejunum is discussed in relation toFIG. 74 .

Diagram 440 depicts ingestible device 65400 within the jejunum, when theperistaltic wave has moved past ingestible device 65400. Diagram 65440depicts contracting portions 65408 that form the peristaltic wave withinthe jejunum having moved past the end of ingestible device 65400. Theperistaltic wave proceeds along the length of the jejunum as differentportions of wall 65406 contract and relax, causing it to appear as ifcontracting portions 65408 of wall 65406 proceed along the length of thejejunum (i.e., as depicted by contracting portions 65408 proceeding fromleft to right in diagrams 65410-65430). While in this position,ingestible device 65400 may detect a similar level of reflectance (e.g.,through the use of illuminator 65124 and detector 65122 of sensingsub-unit 65126 (FIG. 66 )) as detected when there is no peristaltic waveoccurring (e.g., as detected when ingestible device 65400 is in theposition indicated in diagram 65410, or diagram 65420).

Depending on the species of the subject, peristaltic waves may occurwith relatively predictable regularity. After the peristaltic wave haspassed over ingestible device 65400 (e.g., as depicted in diagram65440), the walls 65406 of the jejunum may relax again (e.g., asdepicted in diagram 65410), until the next peristaltic wave begins toform. In some embodiments, ingestible device 65400 may be configured tocontinue to gather reflectance value data while it is within the GItract, and may store a data set with the reflectance values over time.This may allow ingestible device 65400 to detect each of the musclecontractions as the peristaltic wave passes over ingestible device 65400(e.g., as depicted in diagram 65430), and may enable ingestible device65400 to both count the number of muscle contractions that occur, and todetermine that a current location of the ingestible device 65400 iswithin the jejunum. For example, ingestible device 65400 may beconfigured to monitor for possible muscle contractions while is insideeither the stomach or the duodenum, and may determine that ingestibledevice 65400 has moved to the jejunum in response to detecting a musclecontraction consistent with a peristaltic wave.

FIG. 69 is a flowchart illustrating some aspects of a localizationprocess used by the ingestible device. Although FIG. 69 may be describedin connection with the ingestible device 65100 for illustrativepurposes, this is not intended to be limiting, and either portions orthe entirety of the localization procedure 65500 described in FIG. 69may be applied to any device discussed in this application (e.g., theingestible devices 65100, 65300, and 65400), and any of the ingestibledevices may be used to perform one or more parts of the processdescribed in FIG. 69 . Furthermore, the features of FIG. 69 may becombined with any other systems, methods or processes described in thisapplication. For example, portions of the process in FIG. 69 may beintegrated into or combined with the pyloric transition detectionprocedure described by FIG. 70 , or the jejunum detection processdescribed by FIG. 73 .

At 65502, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) gathers measurements (e.g., through detector 65122 (FIG. 66 ))of ambient light. For example, ingestible device 65100 may be configuredto periodically measure (e.g., through detector 65122 (FIG. 66 )) thelevel of ambient light in the environment surrounding ingestible device65100. In some embodiments, the type of ambient light being measured maydepend on the configuration of detector 65122 within ingestible device65100. For example, if detector 65122 is configured to measure red,green, and blue wavelengths of light, ingestible device 65100 may beconfigured to measure the ambient amount of red, green, and blue lightfrom the surrounding environment. In some embodiments, the amount ofambient light measured by ingestible device 65100 will be larger in thearea external to the body (e.g., a well-lit room where ingestible device65100 is being administered to a subject) and in the oral cavity of thesubject, as compared to the ambient level of light measured byingestible device 65100 when inside of an esophagus, stomach, or otherportion of the GI tract (e.g., esophagus 65302, stomach 65306, duodenum65310, or jejunum 65314 (FIG. 67 )).

At 65504, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) determines (e.g., via control circuitry within PCB 65120 (FIG.66 )) whether the ingestible device has detected entry into the GItract. For example, ingestible device 65100 may be configured todetermine when the most recent measurement of ambient light (e.g., themeasurement gathered at 65502) indicates that the ingestible device hasentered the GI tract. For instance, the first time that ingestibledevice 65100 gatherers a measurement of ambient light at 65502,ingestible device 65100 may store that measurement (e.g., via storagecircuitry within PCB 65120 (FIG. 66 )) as a typical level of ambientlight external to the body. Ingestible device 65100 may be configured tothen compare the most recent measurement of ambient light to the typicallevel of ambient light external to the body (e.g., via control circuitrywithin PCB 65120 (FIG. 66 )), and determine that ingestible device 65100has entered the GI tract when the most recent measurement of ambientlight is substantially smaller than the typical level of ambient lightexternal to the body. For example, ingestible device 65100 may beconfigured to detect that it has entered the GI tract in response todetermining that the most recent measurement of ambient light is lessthan or equal to 20% of the typical level of ambient light external tothe body. If ingestible device 65100 determines that it has detectedentry into the GI tract (e.g., that ingestible device 65100 has enteredat least the esophagus 65302 (FIG. 67 )), process 65500 proceeds to65506. Alternately, if ingestible device 65100 determines that it hasnot detected entry into the GI tract (e.g., as a result of the mostrecent measurement being similar to the typical level of ambient lightexternal to the body), process 65500 proceeds back to 65502 where theingestible device 65100 gathers further measurements. For instance,ingestible device 65100 may be configured to wait a predetermined amountof time (e.g., five seconds, ten seconds, etc.), and then gather anothermeasurement of the level of ambient light from the environmentsurrounding ingestible device 65100.

At 65506, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) waits for a transition from the esophagus to the stomach(e.g., from esophagus 65302 to stomach 65306 (FIG. 67 )). For example,ingestible device 65100 may be configured to determine that it hasentered the stomach (e.g., stomach 65306 (FIG. 67 )) after waiting apredetermined period of time after having entered the GI tract. Forinstance, a typical esophageal transit time in a human patient may be onthe order of 15-30 seconds. In this case, after having detected thatingestible device 65100 has entered the GI tract at 65504 (i.e., afterdetecting that ingestible device 65100 has reached at least esophagus65302 (FIG. 67 )), ingestible device 65100 may be configured to wait oneminute, or a similar amount of time longer than the typical esophagealtransmit time (e.g., ninety-seconds), before automatically determiningthat ingestible device 65100 has entered at least the stomach (e.g.,stomach 65306 (FIG. 67 )).

In some embodiments, the ingestible device (e.g., ingestible device65100, 65300, or 65400) may also determine it has entered the stomachbased on measurements of pH or temperature. For example, ingestibledevice 65100 may be configured to determine that it has entered thestomach if a temperature of ingestible device has increased to at least31° C. (i.e., consistent with the temperature inside the stomach), or ifa measured pH of the environment surrounding ingestible device 65100 issufficiently acidic (i.e., consistent with the acidic nature of gastricjuices that may be found inside the stomach).

At 65508, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) stores data indicating the ingestible device has entered thestomach (e.g., stomach 306 (FIG. 67 )). For example, after having waiteda sufficient amount of time at 65506, ingestible device 65100 may storedata (e.g., within storage circuitry of PCB 65120 (FIG. 66 )) indicativeof ingestible device 65100 having entered at least the stomach. Onceingestible device 65100 reaches at least the stomach, process 65500proceeds to 65510 where ingestible device 65100 may be configured togather data to detect entry into the duodenum (e.g., duodenum 65310(FIG. 67 )).

In some embodiments, process 65500 may also simultaneously proceed from65508 to 65520, where ingestible device 65100 may be configured togather data in order to detect muscle contractions and detect entry intothe jejunum (e.g., jejunum 65314 (FIG. 67 )). In some embodiments,ingestible device 65100 may be configured to simultaneously monitor forentry into the duodenum at 65516-65518, as well as detect for entry intothe jejunum at 65520-65524. This may allow ingestible device 65100 todetermine when it has entered the jejunum (e.g., as a result ofdetecting muscle contractions), even when it fails to first detect entryinto the duodenum (e.g., as a result of very quick transit times of theingestible device through the duodenum).

At 65510, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) gathers measurements of green and blue reflectance levels(e.g., through the use of illuminator 65124 and detector 65122 ofsensing sub-unit 65126 (FIG. 66 )) while in the stomach (e.g., stomach65306 (FIG. 67 )). For example, ingestible device 100 may be configuredto periodically gather measurements of green and blue reflectance levelswhile in the stomach. For instance, ingestible device 65100 may beconfigured to transmit a green illumination and a blue illumination(e.g., via illuminator 65124 (FIG. 66 )) every five to fifteen seconds,and measure the resulting reflectance (e.g., via detector 65122 (FIG. 66)). Every time that ingestible device 65100 gathers a new set ofmeasurements, the measurements may be added to a stored data set (e.g.,stored within memory circuitry of PCB 65120 (FIG. 66 )). The ingestibledevice 65100 may then use this data set to determine whether or notingestible device 65100 is still within a stomach (e.g., stomach 65306(FIG. 67 )), or a duodenum (e.g., duodenum 65310 (FIG. 67 )).

In some embodiments, the ingestible device (e.g., ingestible device65100, 65300, or 65400) may be configured to detect a first reflectancebased on generating an illumination of a first wavelength inapproximately the green spectrum of light (between 495-600 nm), anddetecting a second reflectance based on generating an illumination ofthe second wavelength in approximately the blue spectrum of light(between 400-495 nm). In some embodiments, the ingestible device mayensure that the illumination in the green spectrum and the illuminationin the blue spectrum have wavelengths separated by at least 50 nm. Thismay enable ingestible device 65100 to sufficiently distinguish betweenthe two wavelengths when detecting the reflectances (e.g., via detector65122 (FIG. 66 )). It is understood that the separation of 50 nm isintended to be illustrative, and not limiting, and depending on theaccuracy of the detectors within ingestible device 65100, smallerseparations may be possible to be used.

At 65512, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) determines (e.g., using control circuitry within PCB 65120(FIG. 66 )) whether the ingestible device has detected a transition fromthe stomach (e.g., stomach 65306 (FIG. 67 )) to a duodenum (e.g.,duodenum 65310 (FIG. 67 )) based on a ratio of green and blue (G/B)reflectance levels. For example, ingestible device 65100 may obtain(e.g., from memory circuitry of PCB 65120 (FIG. 66 )) a data setcontaining historical data for the respective ratio of the greenreflectance to the blue reflectance as measured at a respective time.Generally speaking, a duodenum (e.g., duodenum 65310 (FIG. 67 )) of ahuman subject reflects a higher ratio of green light to blue light, ascompared to the ratio of green light to blue light that is reflected bya stomach (e.g., stomach 65306 (FIG. 67 )). Based on this, ingestibledevice 65100 may be configured to take a first set of ratios from thedata set, representing the result of recent measurements, and comparethem to a second set of ratios from the data set, representing theresults of past measurements. When the ingestible device 65100determines that the mean value of the first set of ratios issubstantially larger than the mean value of the second set of ratios(i.e., that the ratio of reflected green light to reflected blue lighthas increased), the ingestible device 65100 may determine that it hasentered the duodenum (e.g., duodenum 65310 (FIG. 67 )) from the stomach(e.g., stomach 65306 (FIG. 66 )). If the ingestible device 65100 detectsa transition from the stomach (e.g., stomach 65306 (FIG. 67 )) to aduodenum (e.g., duodenum 65310 (FIG. 67 )), process 65500 proceeds to65514, where ingestible device 65100 stores data indicating that theingestible device 65100 has entered the duodenum (e.g., duodenum 65310(FIG. 67 )). Alternatively, if the ingestible device determines that theingestible device has not transitioned from the stomach (e.g., stomach65306 (FIG. 67 )) to the duodenum (e.g., duodenum 65310 (FIG. 67 )),process 65500 proceeds back to 65510 to gather more measurements ofgreen and blue reflectance levels while still in the stomach (e.g.,stomach 65306 (FIG. 67 )). An example procedure for using measurementsof green and blue reflectances to monitor for transitions between thestomach and the duodenum is discussed in greater detail in relation toFIG. 70 .

In some embodiments, the first time that ingestible device 65100 detectsa transition from the stomach (e.g., stomach 65306 (FIG. 67 )) to theduodenum (e.g., duodenum 65310 (FIG. 67 )), ingestible device 65100 maybe configured to take a mean of the second set of data, (e.g., the setof data previously recorded while in stomach 65306 (FIG. 67 )) and storethis as a typical ratio of green light to blue light detected within thestomach (e.g., stomach 65306 (FIG. 67 )) (e.g., within memory circuitryof PCB 65120 (FIG. 67 )). This stored information may later be used byingestible device 65100 to determine when ingestible device 65100re-enters the stomach (e.g., stomach 65306 (FIG. 67 )) from the duodenum(e.g., duodenum 65310 (FIG. 67 )) as a result of a reverse pylorictransition.

At 65514, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) stores data indicating that the ingestible device has enteredthe duodenum (e.g., duodenum 65310 (FIG. 67 )). For example, ingestibledevice 65100 may store a flag within local memory (e.g., memorycircuitry of PCB 65120) indicating that the ingestible device 65100 iscurrently in the duodenum. In some embodiments, the ingestible device65100 may also store a timestamp indicating the time when ingestibledevice 65100 entered the duodenum. Once ingestible device 65100 reachesthe duodenum, process 65500 proceeds to 65520 where ingestible device65100 may be configured to gather data in order to detect musclecontractions and detect entry into the jejunum (e.g., jejunum 65314(FIG. 67 )). Process 65500 also proceeds from 65514 to 65516, whereingestible device 65100 may be configured to gather data additional datain order to detect re-entry into the stomach (e.g., stomach 65306 (FIG.67 )) from the duodenum (e.g., duodenum 65310 (FIG. 67 )).

At 65516, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) gathers measurements (e.g., via sensing sub-unit 65126 (FIG.66 )) of green and blue reflectance levels while in the duodenum (e.g.,duodenum 65310 (FIG. 67 )). For example, ingestible device 65100 may beconfigured to periodically gather measurements (e.g., via sensingsub-unit 65126 (FIG. 66 )) of green and blue reflectance levels while inthe duodenum, similar to the measurements made at 65510 while in thestomach. For instance, ingestible device 65100 may be configured totransmit a green illumination and a blue illumination (e.g., viailluminator 65124 (FIG. 66 )) every five to fifteen seconds, and measurethe resulting reflectance (e.g., via detector 65122 (FIG. 66 )). Everytime that ingestible device 65100 gathers a new set of measurements, themeasurements may be added to a stored data set (e.g., stored withinmemory circuitry of PCB 65120 (FIG. 66 )). The ingestible device 65100may then use this data set to determine whether or not ingestible device65100 is still within the duodenum (e.g., duodenum 65310 (FIG. 67 )), orif the ingestible device 65100 has transitioned back into the stomach(e.g., stomach 65306 (FIG. 67 )).

At 65518, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) determines a transition from the duodenum (e.g., duodenum65310 (FIG. 67 )) to the stomach (e.g., stomach 65306 (FIG. 67 )) basedon a ratio of the measured green reflectance levels to the measured bluereflectance levels. In some embodiments, ingestible device 65100 maycompare the ratio of the measured green reflectance levels to themeasured blue reflectance levels recently gathered by ingestible device65100 (e.g., measurements gathered at 65516), and determine whether ornot the ratio of the measured green reflectance levels to the measuredblue reflectance levels is similar to the average ratio of the measuredgreen reflectance levels to the measured blue reflectance levels seen inthe stomach (e.g., stomach 65306 (FIG. 67 )). For instance, ingestibledevice 65100 may retrieve data (e.g., from memory circuitry of PCB 65120(FIG. 66 )) indicative of the average ratio of the measured greenreflectance levels to the measured blue reflectance levels seen in thestomach, and determine that ingestible device 65100 has transitionedback to the stomach if the recently measured ratio of the measured greenreflectance levels to the measured blue reflectance levels issufficiently similar to the average level in the stomach (e.g., within20% of the average ratio of the measured green reflectance levels to themeasured blue reflectance levels seen in the stomach, or within anyother suitable threshold level). If the ingestible device detects atransition from the duodenum (e.g., duodenum 65310 (FIG. 67 )) to thestomach (e.g., stomach 65306 (FIG. 67 )), process 65500 proceeds to65508 to store data indicating the ingestible device has entered thestomach (e.g., stomach 65306 (FIG. 67 )), and continues to monitor forfurther transitions. Alternatively, if the ingestible device does notdetect a transition from the duodenum (e.g., duodenum 65310 (FIG. 67 ))to the stomach (e.g., stomach 65306 (FIG. 67 )), process 65500 proceedsto 65516 to gather additional measurements of green and blue reflectancelevels while in the duodenum (e.g., duodenum 65310 (FIG. 67 )), whichmay be used to continuously monitor for possible transitions back intothe stomach. An example procedure for using measurements of green andblue reflectances to monitor for transitions between the stomach and theduodenum is discussed in greater detail in relation to FIG. 70 .

At 65520, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) gathers periodic measurements of the reflectance levels (e.g.,via sensing sub-unit 65126 (FIG. 66 )) while in the duodenum (e.g.,duodenum 65310 (FIG. 67 )). In some embodiments, the ingestible device(e.g., ingestible device 65100, 65300, or 65400) may gather similarperiodic measurements while in the stomach as well. In some embodiments,these periodic measurements may enable ingestible device 65100 to detectmuscle contractions (e.g., muscle contractions due to a peristaltic waveas discussed in relation to FIG. 68 ), which may be indicative of entryinto a jejunum (e.g., jejunum 65314 (FIG. 67 )). Ingestible device 65100may be configured to gather periodic measurements using any suitablewavelength of illumination (e.g., by generating illumination usingilluminator 65124, and detecting the resulting reflectance usingdetector 65122 (FIG. 66 )), or combinations of wavelengths ofillumination. For example, in some embodiments, ingestible device 65100may be configured to generate red, green, and blue illumination, storeseparate data sets indicative of red, green, and blue illumination, andanalyze each of the data sets separately to search for frequencycomponents in the recorded data indicative of detected musclecontractions. In some embodiments, the measurements gathered byingestible device 65100 at 65520 may be sufficiently fast as to detectperistaltic waves in a subject. For instance, in a healthy humansubject, peristaltic waves may occur at a rate of approximately 0.05 Hzto 0.33 Hz. Therefore, the ingestible device 65400 may be configured togenerate illumination and measure the resulting reflectance at leastonce every 2.5 seconds (i.e., potentially minimum rate to detect a 0.2Hz signal), and preferably at a higher rate, such as once every 0.5seconds or faster, and store values indicative of the resultingreflectances in a data set (e.g., within memory circuitry of PCB 65120(FIG. 66 )). After gathering additional data (e.g., after gathering onenew data point, or a predetermined number of new data points), process65500 proceeds to 65522, where ingestible device 65100 determineswhether or not a muscle contraction has been detected.

At 65522, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) determines (e.g., via control circuitry within PCB 65120 (FIG.66 )) whether the ingestible device detects a muscle contraction basedon the measurements of reflectance levels (e.g., as gathered by sensingsub-unit 65126 (FIG. 66 )). For example, ingestible device 65100 mayobtain a fixed amount of data stored as a result of measurements made at65520 (e.g., retrieve the past minute of data from memory circuitrywithin PCB 65120 (FIG. 66 )). Ingestible device 65100 may then convertthe obtained data into the frequency domain, and search for peaks in afrequency range that would be consistent with peristaltic waves. Forexample, in a healthy human subject, peristaltic waves may occur at arate of approximately 0.05 Hz to 0.33 Hz, and an ingestible device 65100may be configured to search for peaks in the frequency domainrepresentation of the data between 0.05 Hz to 0.33 Hz above a thresholdvalue. If the ingestible device 65100 detects a contraction based on thereflectance levels (e.g., based on detecting peaks in the frequencydomain representation of the data between 0.05 Hz to 0.33 Hz), process65500 proceeds to 65524 to store data indicating that the device hasentered the jejunum. Alternatively, if the ingestible device 65100 doesnot detect a muscle contraction, process 65500 proceeds to 65520 togather periodic measurements of the reflectance levels while in theduodenum (e.g., duodenum 65310 (FIG. 67 )). In some embodiments, theingestible device (e.g., ingestible device 65100, 65300, or 65400) maystore data (e.g., within memory circuitry of PCB 65120 (FIG. 66 ))indicating that a muscle contraction was detected, and process 65500will not proceed from 65522 to 65524 until a sufficient number of musclecontractions have been detected.

At 65524, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) stores data (e.g., within memory circuitry of PCB 65120 (FIG.66 )) indicating that the device has entered the jejunum (e.g., jejunum65314 (FIG. 67 )). For example, in response to detecting that musclecontraction has occurred at 65522, ingestible device 65100 may determinethat it has entered the jejunum 65314, and is no longer inside of theduodenum (e.g., duodenum 65310 (FIG. 67 )) or the stomach (e.g., stomach65306 (FIG. 67 )). In some embodiments, the ingestible device 65100 maycontinue to measure muscle contractions while in the jejunum, and maystore data indicative of the frequency, number, or strength of themuscle contractions over time (e.g., within memory circuitry of PCB65120 (FIG. 66 )). In some embodiments, the ingestible device 65100 mayalso be configured to monitor for one or more transitions. Suchtransitions can include a transition from the jejunum to the ileum, anileoceacal transition from the ileum to the cecum, a transition from thececum to the colon, or detect exit from the body (e.g., by measuringreflectances, temperature, or levels of ambient light).

In some embodiments, the ingestible device (e.g., ingestible device65100, 65300, or 65400) may also determine that it has entered thejejunum (e.g., jejunum 65314 (FIG. 67 )) after a pre-determined amountof time has passed after having detected entry into the duodenum (e.g.,duodenum 65310 (FIG. 67 )). For example, barring a reverse pylorictransition from the duodenum (e.g., duodenum 65310 (FIG. 67 )) back tothe stomach (e.g., stomach 65306 (FIG. 67 )), the typical transit timefor an ingestible device to reach the jejunum from the duodenum in ahealthy human subject is less than three minutes. In some embodiments,the ingestible device (e.g., ingestible device 65100, 65300, or 65400)may therefore be configured to automatically determine that it hasentered the jejunum after spending at least three minutes within theduodenum. This determination may be made separately from thedetermination made based on measured muscle contractions (e.g., thedetermination made at 65522), and in some embodiments, ingestible device65100 may determine that it has entered the jejunum in response toeither detecting muscle contractions, or after three minutes has elapsedfrom having entered the duodenum (e.g., as determined by storing data at65514 indicative of the time that ingestible device entered theduodenum).

For illustrative purposes, 65512-65518 of process 65500 describe theingestible device (e.g., ingestible device 65100, 65300, or 65400)measuring green reflectances and blue reflectances, calculating a ratioof the two reflectances, and using this information to determine whenthe ingestible device has transitioned between the duodenum and stomach.However, in some embodiments, other wavelengths of light may be usedother than green and blue, provided that the wavelengths of light chosenhave different reflective properties within the stomach and the duodenum(e.g., as a result of different reflection coefficients of the stomachtissue and the tissue of the duodenum).

It will be understood that the steps and descriptions of the flowchartsof this disclosure, including FIG. 69 , are merely illustrative. Any ofthe steps and descriptions of the flowcharts, including FIG. 69 , may bemodified, omitted, rearranged, and performed in alternate orders or inparallel, two or more of the steps may be combined, or any additionalsteps may be added, without departing from the scope of the presentdisclosure. For example, the ingestible device 65100 may calculate themean and the standard deviation of multiple data sets in parallel inorder to speed up the overall computation time. As another example,ingestible device 65100 may gather data periodic measurements and detectpossible muscle contractions (e.g., at 65520-65522) while simultaneouslygathering green and blue reflectance levels to determine transitions toand from the stomach and duodenum (e.g., at 65510-65518). Furthermore,it should be noted that the steps and descriptions of FIG. 69 may becombined with any other system, device, or method described in thisapplication, including processes 65600 (FIG. 70 ) and 65900 (FIG. 73 ),and any of the ingestible devices or systems discussed in thisapplication (e.g., ingestible devices 65100, 65300, or 65400) could beused to perform one or more of the steps in FIG. 69 .

FIG. 70 is a flowchart illustrating some aspects of a process fordetecting transitions from a stomach to a duodenum and from a duodenumback to a stomach, which may be used when determining a location of aningestible device as it transits through a gastrointestinal (GI) tract,in accordance with some embodiments of the disclosure. In someembodiments, process 65600 may begin when an ingestible device firstdetects that it has entered the stomach, and will continue as long asthe ingestible device determines that it is within the stomach or theduodenum. In some embodiments, process 65600 may only be terminated whenan ingestible device determines that it has entered the jejunum, orotherwise progressed past the duodenum and the stomach. Although FIG. 70may be described in connection with the ingestible device 65100 forillustrative purposes, this is not intended to be limiting, and eitherportions or the entirety of the duodenum detection process 65600described in FIG. 70 may be applied to any device discussed in thisapplication (e.g., the ingestible devices 65100, 65300, or 65400), andany of the ingestible devices may be used to perform one or more partsof the process described in FIG. 70 . Furthermore, the features of FIG.70 may be combined with any other systems, methods or processesdescribed in this application. For example, portions of the processdescribed by the process in FIG. 70 may be integrated into process 65500discussed in relation to FIG. 69 .

At 65602, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) retrieves a data set (e.g., from memory circuitry within PCB65120 (FIG. 66 )) with ratios of the measured green reflectance levelsto the measured blue reflectance levels over time. For example,ingestible device 65100 may retrieve a data set from PCB 65120containing recently recorded ratios of the measured green reflectancelevels to the measured blue reflectance levels (e.g., as recorded at65510 or 65516 of process 65500 (FIG. 69 )). In some embodiments, theretrieved data set may include the ratios of the measured greenreflectance levels to the measured blue reflectance levels over time.Example plots of data sets of ratios of the measured green reflectancelevels to the measured blue reflectance levels are discussed further inrelation to FIG. 71 and FIG. 72 .

At 65604, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) includes a new measurement (e.g., as made with sensingsub-unit 65126 (FIG. 66 )) of a ratio of the measured green reflectancelevel to the measured blue reflectance level in the data set. Forexample, ingestible device 65100 may be configured to occasionallyrecord new data by transmitting green and blue illumination (e.g., viailluminator 65124 (FIG. 66 )), detecting the amount of reflectancereceived due to the green and blue illumination (e.g., via detector65122 (FIG. 66 )), and storing data indicative of the amount of thereceived reflectance (e.g., in memory circuitry of PCB 65120 (FIG. 66)). The ingestible device 65100 may be configured to record new dataevery five to fifteen seconds, or at any other convenient interval oftime. For illustrative purposes, ingestible device 65100 is described asstoring and retrieving the ratio of the measured green reflectancelevels to the measured blue reflectance levels (e.g., if the amount ofdetected green reflectance was identical to the amount of detected bluereflectance at a given time, the ratio of the green and bluereflectances would be “1.0” at that given time); however, it isunderstood that the green reflectance data and the blue reflectance datamay be stored separately within the memory of ingestible device 65100(e.g., stored as two separate data sets within memory circuitry of PCB65120 (FIG. 66 )).

At 65606, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) retrieves a first subset of recent data by applying a firstsliding window filter to the data set. For example, ingestible device65100 may use a sliding window filter to obtain a predetermined amountof the most recent data within the data set, which may include any newvalues of the ratio of the measured green reflectance level to themeasured blue reflectance level obtained at 65604. For instance, theingestible device may be configured to select between ten and forty datapoints from the data set, or ingestible device 65100 may be configuredto select a predetermined range of data values between fifteen secondsof data and five minutes of data. In some embodiments, other ranges ofdata may be selected, depending on how frequently measurements arerecorded, and the particular application at hand. For instance, anysuitable amount of data may be selected in the sliding window, providedthat it is sufficient to detect statistically significant differencesbetween the data selected in a second sliding window (e.g., the secondsubset of data selected at 65614).

In some embodiments, the ingestible device (e.g., ingestible device65100, 65300, or 65400) may also be configured to remove outliers fromthe data set, or to smooth out unwanted noise in the data set. Forexample, ingestible device 65100 may select the first subset of data, orany other subset of data, by first obtaining a raw set of values byapplying a window filter to the data set (e.g., selecting a particularrange of data to be included). Ingestible device 65100 may then beconfigured to identify outliers in the raw set of values; for instance,by identifying data points that are over three standard deviations awayfrom the mean value of the raw set of values, or any other suitablethreshold. Ingestible device 65100 may then determine the subset of databy removing outliers from the raw set of values. This may enableingestible device 65100 to avoid spurious information when determiningwhether or not it is located within the stomach or the duodenum.

At 65608, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) determines whether the most recently detected location was theduodenum (e.g., duodenum 65310 (FIG. 67 )). In some embodiments,ingestible device 65100 may store a data flag (e.g., within memorycircuitry of PCB 65120 (FIG. 66 )) indicating the most recent portion ofthe GI tract that the ingestible device 65100 detected itself to bewithin. For instance, every time ingestible device 65100 detects entryto the stomach (e.g., detects entry into stomach 65306 (FIG. 67 ) as aresult of the decision made at 65610), a flag is stored in memoryindicating the ingestible device 65100 is in the stomach (e.g., as partof storing data at 65612). If ingestible device 65100 subsequentlydetects entry into the duodenum (e.g., detects entry into duodenum 65310(FIG. 67 ) as a result of a decision made at 65624), another differentflag is stored in memory indicating that the ingestible device 65100 isin the duodenum (e.g., as part of storing data at 65624). In this case,ingestible device 65100 may retrieve the most recently stored flag at65608, and determine whether or not the flag indicates that theingestible device 65100 was most recently within the duodenum. Ifingestible device 65100 detects that it was most recently in theduodenum, process 65600 proceeds to 65610 where the ingestible devicecompares the recent measurements of the ratios of the measured greenreflectance levels to the measured blue reflectance levels (e.g.,measurements that include the recent measurement made at 65606) to thetypical ratios measured within the stomach, and uses this information todetermine whether a reverse pyloric transition from the duodenum back tothe stomach has occurred. Alternately, if ingestible device 65100detects that it was not most recently in the duodenum (e.g., because itwas in the stomach instead), process 65600 proceeds to 65614 where theingestible device compares the recent measurements of the ratios of themeasured green reflectance levels to the measured blue reflectancelevels (e.g., measurements that include the recent measurement made at65606) to past measurements, and uses this information to determinewhether a pyloric transition from the stomach to the duodenum hasoccurred.

Process 65600 proceeds from 65608 to 65610 when the ingestible devicedetermined that it was most recently in the duodenum. At 65610, theingestible device (e.g., ingestible device 65100, 65300, or 65400)determines (e.g., via control circuitry within PCB 65120 (FIG. 66 ))whether the current G/B signal is similar to a recorded average G/Bsignal in the stomach. For example, ingestible device 65100 may beconfigured to have previously stored data (e.g., within memory circuitryof PCB 65120 (FIG. 66 )) indicative of the average ratio of the measuredgreen reflectance levels to the measured blue reflectance levelsmeasured in the stomach. Ingestible device 65100 may then retrieve thisstored data indicative of the average ratio of the measured greenreflectance levels to the measured blue reflectance levels in thestomach, and compare this against the recent measurements in order todetermine whether or not ingestible device 65100 has returned back tothe stomach from the duodenum. For instance, ingestible device 65100 maydetermine if the mean value of the first subset of recent data (i.e.,the average value of the recently measured ratios of the measured greenreflectance levels to the measured blue reflectance levels) is less thanthe average ratio of the measured green reflectance levels to themeasured blue reflectance levels within the stomach, or less that theaverage ratio measured within the stomach plus a predetermined numbertimes the standard deviation of the ratios measured within the stomach.For instance, if the average ratio of the measured green reflectancelevels to the measured blue reflectance levels in the stomach was “1,”with a standard deviation of “0.2,” ingestible device 100 may determinewhether or not the mean value of the first subset of data is less than“1.0 + k*0.2,” where “k” is a number between zero and five. It isunderstood that, in some embodiments, the ingestible device 65100 may beconfigured to use a different threshold level to determine whether ornot the mean value of the first subset of recent data is sufficientlysimilar to the average ratio of the measured green reflectance levels tothe measured blue reflectance levels within the stomach. In response todetermining that the recent ratio of the measured green reflectancelevels to the measured blue reflectance levels is similar to the averageratio of measured green and blue reflectance levels seen in the stomach,process 65600 proceeds to 65612 where ingestible device 65100 storesdata indicating that it has re-entered the stomach from the duodenum.Alternately, in response to determining that the recent ratio ofmeasured green and blue reflectance levels is sufficiently differentfrom the average ratio of measured green and blue reflectance levelsseen in the stomach, ingestible device 65100 proceeds directly to 65604,and continues to obtain new data on an ongoing basis.

At 65612, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) stores data indicating a reverse pyloric transition from theduodenum to the stomach was detected. For example, ingestible device65100 may store a data flag (e.g., within memory circuitry of PCB 65120(FIG. 66 )) indicating that the ingestible device 65100 most recentlydetected itself to be within the stomach portion of the GI tract (e.g.,stomach 65306 (FIG. 67 )). In some embodiments, ingestible device 65100may also store data (e.g., within memory circuitry of PCB 65120 (FIG. 66)) indicating a time that ingestible device 65100 detected the reversepyloric transition from the duodenum to the stomach. This informationmay be used by ingestible device 65100 at 65608, and as a result process65600 may proceed from 65608 to 65614, rather than proceeding from 65618to 65610. After ingestible device 65100 stores the data indicating areverse pyloric transition from the duodenum to the stomach wasdetected, process 65600 proceeds to 65604 where ingestible device 65100continues to gather additional measurements, and continues to monitorfor further transitions between the stomach and the duodenum.

Process 65600 proceeds from 65608 to 65614 when the ingestible devicedetermined that it was not most recently in the duodenum (e.g., as aresult of having most recently been in the stomach instead). At 65614,the ingestible device (e.g., ingestible device 65100, 65300, or 65400)retrieves a second subset of previous data by applying a second slidingwindow filter to the data set. For example, ingestible device 65100 mayuse a sliding window filter to obtain a predetermined amount of olderdata from a past time range, which may be separated from recent timerange used to select the first subset of data gathered at 65606 by apredetermined period of time. In some embodiments, any suitable amountof data may be selected by the first and second window filters, and thefirst and second window filters may be separated by any appropriatepredetermined amount of time. For example, in some embodiments, thefirst window filter and the second window filter may each be configuredto select a predetermined range of data values from the data set, thepredetermined range being between fifteen seconds of data and fiveminutes of data. In some embodiments, the recent measurements and thepast measurements may then be separated by a predetermined period oftime that is between one to five times the predetermined range of datavalues. For instance, ingestible device 65100 may select the firstsubset of data and the second subset of data to each be one minute ofdata selected from the dataset (i.e., selected to have a predeterminedrange of one minute), and the first subset of data and the second subsetof data are selected from recorded measurements that are at least twominutes apart (i.e., the predetermined period of time is two minutes,which is twice the range used to select the subsets of data using thewindow filters). As another example, ingestible device 100 may selectthe first subset of data and the second subset of data to each be fiveminutes of data selected from the dataset (i.e., selected to have apredetermined range of five minutes), and the first subset of data andthe second subset of data are selected from recorded measurements thatare at least 10 minutes apart (i.e., the predetermined period of time istwo minutes, which is twice the range used to select the subsets of datausing the window filters).

In some embodiments, if ingestible device 65100 recently transitioned tothe stomach from the duodenum (e.g., as determined by checking forrecent data stored within ingestible device 65100 at 65612), ingestibledevice 65100 may select the second subset of data at 65614 from a timeframe when ingestible device 65100 is known to be within the stomach. Insome embodiments, ingestible device 65100 may alternately select apreviously recorded average and standard deviation for ratios of greenreflectances and blue reflectances within the stomach (e.g., an averageand standard deviation typical of data recorded within the stomach, aspreviously recorded within memory circuitry of PCB 65120 at 65620) inplace of the second subset of data. In this case, ingestible device65100 may simply use the previously recorded average and previouslyrecorded standard deviation when making a determination at 65616, ratherthan expending resources to calculate the mean and standard deviation ofthe second subset.

At 65616, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) determines whether the difference between the mean of thesecond subset and the mean of the first subset is greater than apredetermined multiple of the standard deviation of the first subset.For example, ingestible device 65100 may compute a difference between amean of the first subset of recent data and a mean of a second subset ofpast data, and determine whether this difference is greater than threetimes the standard deviation of the second subset of past data. In someembodiments, it is understood that any convenient threshold level may beused other than three times the standard deviation, such as any valuebetween one and five times the standard deviation. Also, in someembodiments, the ingestible device may instead set the threshold levelbased on the standard deviation of the second subset instead of thefirst subset. In response to determining that the difference between themean of the first subset and the mean of the second subset is greaterthan a predetermined multiple of the standard deviation of the secondsubset, process 65600 proceeds to 65618. Otherwise, process 65600proceeds back to 65604, where the ingestible device 65604 continues togather new data to be used in monitoring for transitions between thestomach (e.g., stomach 65306 (FIG. 67 )) and the duodenum (e.g.,duodenum 65310 (FIG. 67 )).

At 65618, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) determines (e.g., via control circuitry within PCB 65120 (FIG.66 )) whether the determination made at 65616 is the first time that thedifference between the mean of the first subset of recent data and themean of the second subset of past data is calculated to be greater thanthe standard deviation of the second subset. If the ingestible devicedetermines that this is the first time that the difference between themean of the first subset and the mean of the second subset is calculatedto be greater than the standard deviation of the second subset, process65600 proceeds to 65620 to store the mean of the second subset of pastdata as an average G/B signal in the stomach. Alternatively, if theingestible device determines that the immediately precedingdetermination made at 65616 is not the first time that the differencebetween the mean of the first subset of recent data and the mean of thesecond subset of past data is calculated to be greater than the standarddeviation of the second subset, process 65600 proceeds directly to65622.

At 65620, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) stores the mean of the second subset as an average G/B signalin the stomach. For example, ingestible device 65100 may be configuredto store the mean of the second subset of past data (e.g., store withinmemory circuitry of PCB 65120 (FIG. 66 )) as the average ratio of themeasured green reflectance levels to the measured blue reflectancelevels measured in the stomach. In some embodiments, ingestible device65100 may also store the standard deviation of the second subset of pastdata as a typical standard deviation of the ratios of the measured greenreflectance levels to the measured blue reflectance levels detectedwithin the stomach. This stored information may be used by theingestible device later on (e.g., at 65610) to compare against futuredata, which may enable the ingestible device to detect reverse pylorictransitions from the duodenum (e.g., duodenum 65310 (FIG. 67 )) back tothe stomach (e.g., stomach 65306 (FIG. 67 )), and may generally be usedin place of other experimental data gathered from the stomach (e.g., inplace of the second subset of data at 65616). After storing the mean ofthe second subset as an average G/B signal in the stomach, process 65600proceeds to 65622.

At 65622, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) determines whether a difference of the mean of the firstsubset of recent data to the mean of the second subset of past data isgreater than a predetermined threshold, “M”. In some embodiments, thepredetermined threshold, “M,” will be sufficiently large to ensure thatthe mean of the first subset is substantially larger than the mean ofthe second subset, and may enable ingestible device 65100 to ensure thatit detected an actual transition to the duodenum. This may beparticularly advantageous when the determination made at 65616 ispotentially unreliable due to the standard deviation of the secondsubset of past data being abnormally small. For example, a typical valueof the predetermined threshold “M,” may be on the order of 0.1 to 0.5.If ingestible device 65100 determines that the difference of the mean ofthe first subset of recent data to the second subset of past data isgreater than a predetermined threshold, process 65600 proceeds to 65624to store data indicating that a pyloric transition from the stomach tothe duodenum (e.g., from stomach 65306 to duodenum 65310 (FIG. 67 )) wasdetected. Alternatively, if the ingestible device determines that theratio of the mean of the first subset to the second subset is less thanor equal to the predetermined threshold, “M” (i.e., determines that atransition to the duodenum has not occurred), process 65600 proceedsdirectly to 65604 where ingestible device 65100 continues to make newmeasurements and monitor for possible transitions between the stomachand the duodenum.

In some embodiments, instead of using a difference of the mean of thefirst subset of recent data to the mean of the second subset of pastdata, the ingestible device (e.g., ingestible device 65100, 65300, or65400) determines whether the ratio of the mean of the first subset ofrecent data to the mean of the second subset of past data is greaterthan a predetermined threshold, “M”. In some embodiments, thepredetermined threshold, “M,” will be sufficiently large to ensure thatthe mean of the first subset is substantially larger than the mean ofthe second subset, and may enable ingestible device 65100 to ensure thatit detected an actual transition to the duodenum. This may beparticularly advantageous when the determination made at 65616 ispotentially unreliable due to the standard deviation of the secondsubset of past data being abnormally small. For example, a typical valueof the predetermined threshold “M,” may be on the order of 1.2 to 2.0.It is understood any convenient type of threshold or calculation may beused to determine whether or not the first subset of data and the secondsubset of data are both statistically distinct from one another, andalso substantially different from one another in terms of overallaverage value.

At 65624, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) stores data indicating a pyloric transition from the stomachto the duodenum was detected. For example, ingestible device 65100 maystore a data flag (e.g., within memory circuitry of PCB 65120 (FIG. 66)) indicating that the ingestible device 65100 most recently detecteditself to be within the duodenum portion of the GI tract (e.g., duodenum65310 (FIG. 67 )). In some embodiments, ingestible device 65100 may alsostore data (e.g., within memory circuitry of PCB 65120 (FIG. 66 ))indicating a time that ingestible device 65100 detected the pylorictransition from the stomach to the duodenum. This information may beused by ingestible device 65100 at 65608, and as a result process 65600may proceed from 65608 to 65610, rather than proceeding from 65618 to65614. After ingestible device 65100 stores the data indicating apyloric transition from the stomach to the duodenum was detected,process 65600 proceeds to 65604 where ingestible device 65100 continuesto gather additional measurements, and continues to monitor for furthertransitions between the stomach and the duodenum.

It will be understood that the steps and descriptions of the flowchartsof this disclosure, including FIG. 70 , are merely illustrative. Any ofthe steps and descriptions of the flowcharts, including FIG. 70 , may bemodified, omitted, rearranged, and performed in alternate orders or inparallel, two or more of the steps may be combined, or any additionalsteps may be added, without departing from the scope of the presentdisclosure. For example, the ingestible device 65100 may calculate themean and the standard deviation of multiple data sets in parallel inorder to speed up the overall computation time. Furthermore, it shouldbe noted that the steps and descriptions of FIG. 70 may be combined withany other system, device, or method described in this application, andany of the ingestible devices or systems discussed in this applicationcould be used to perform one or more of the steps in FIG. 70 . Forexample, portions of process 65600 may be incorporated into 65508-65516of process 65500 (FIG. 69 ), and may be part of a more general processfor determining a location of the ingestible device. As another example,the ratio of detected blue and green light (e.g., as measured and addedto the data set at 65604) may continue even outside of the stomach orduodenum, and similar information may be recorded by the ingestibledevice throughout its transit in the GI tract. Example plots of datasets of ratios of measured green and blue reflectance levels, which maybe gathered throughout the GI tract, are discussed further in relationto FIG. 71 and FIG. 72 below.

FIG. 71 is a plot illustrating data collected during an exampleoperation of an ingestible device (e.g., ingestible device 65100, 65300,or 65400), which may be used when determining a location of aningestible device as it transits through a gastrointestinal (GI) tract,in accordance with some embodiments of the disclosure.

Although FIG. 71 may be described in connection with ingestible device65100 for illustrative purposes, this is not intended to be limiting,and plot 65700 and data set 65702 may be typical of data gathered by anydevice discussed in this application. Plot 65700 depicts the ratios ofthe measured green reflectance levels to the measured blue reflectancelevels over time. For example, ingestible device 65100 may have computedthe value for each point in the data set 65702 by transmitting green andblue illumination at a given time (e.g., via illuminator 65124 (FIG. 66)), measuring the resulting green and blue reflectances (e.g., viadetector 65122 (FIG. 66 )), calculating the ratio of the resultingreflectances, and storing the ratio in the data set along with atimestamp indicating the time that the reflectances were gathered.

At 65704, shortly after ingestible device 65100 begins operation,ingestible device 65100 determines that it has reached at least thestomach (e.g., as a result of making a determination similar to thedetermination discussed in relation to 65506 in process 65500 (FIG. 69)). Ingestible device 65100 continues to gather additional measurementsof green and blue reflectance levels, and at 65706 ingestible device65100 determines that a pyloric transition has occurred from the stomachto the duodenum (e.g., as a result of making a determination similar tothe determinations discussed in relation to 65616-65624 of process 65600(FIG. 70 )). Notably, the values in data set 65702 around 65706 jump upprecipitously, which is indicative of the higher ratios of measuredgreen reflectance levels to measured blue reflectance levels typical ofthe duodenum.

The remainder of the data set 65702 depicts the ratios of the measuredgreen reflectance levels to the measured blue reflectance levelsthroughout the remainder of the GI tract. At 65708, ingestible device65100 has reached the jejunum (e.g., as determined through measurementsof muscle contractions, as discussed in relation to FIG. 73 ), and by65710, ingestible device 65100 has reached the cecum. It is understoodthat, in some embodiments, the overall character and appearance of dataset 65702 changes within the small intestine (i.e., the duodenum,jejunum, and ileum) versus the cecum. Within the jejunum and ileum,there may typically be a wide variation in the ratios of the measuredgreen reflectance levels to the measured blue reflectance levels,resulting in relatively noisy data with a high standard deviation. Bycomparison, within the cecum ingestible device 65100 may measure arelatively stable ratio of the measured green reflectance levels to themeasured blue reflectance levels. In some embodiments, ingestible device65100 may be configured to determine transitions from the smallintestine to the cecum based on these differences. For example,ingestible device 65100 may compare recent windows of data to pastwindows of data, and detect a transition to the cecum in response todetermining that the standard deviation of the ratios in the recentwindow of data is substantially less than the standard deviation of theratios in the past window of data.

FIG. 72 is another plot illustrating data collected during an exampleoperation of an ingestible device, which may be used when determining alocation of an ingestible device as it transits through agastrointestinal (GI) tract, in accordance with some embodiments of thedisclosure. Similar to FIG. 71 , FIG. 72 may be described in connectionwith the ingestible device 65100 for illustrative purposes. However,this is not intended to be limiting, and plot 65800 and data set 65802may be typical of data gathered by any device discussed in thisapplication.

At 65804, shortly after ingestible device 65100 begins operation,ingestible device 65100 determines that it has reached at least thestomach (e.g., as a result of making a determination similar to thedetermination discussed in relation to 65506 in process 500 (FIG. 69 )).Ingestible device 65100 continues to gather additional measurements ofgreen and blue reflectance levels (e.g., via sensing sub-unit 65126(FIG. 66 )), and at 65806 ingestible device 65100 determines that apyloric transition has occurred from the stomach to the duodenum (e.g.,as a result of making a determination similar to the determinationsdiscussed in relation to 65616-65624 of process 65600 (FIG. 70 )).Notably, the values in data set 65802 around 65806 jump upprecipitously, which is indicative of the higher ratios of measuredgreen reflectance levels to measured blue reflectance levels typical ofthe duodenum, before falling shortly thereafter. As a result of thereduced values in data set 65802, ingestible device 65100 determinesthat a reverse pyloric transition has occurred from the duodenum back tothe stomach at 65808 (e.g., as a result of making a determinationsimilar to the determinations discussed in relation to 65610-65612 ofprocess 65600 (FIG. 70 )). At 65810, as a result of the values in dataset 65802 increasing again, ingestible device 65100 determines thatanother pyloric transition has occurred from the stomach to theduodenum, and shortly thereafter ingestible device 65100 proceedsonwards to the jejunum, ileum, and cecum.

The remainder of the data set 65802 depicts the ratios of the measuredgreen reflectance levels to the measured blue reflectance levelsthroughout the remainder of the GI tract. Notably, at 65812, ingestibledevice reaches the transition point between the ileum and the cecum. Asdiscussed above in relation to FIG. 71 , the transition to the cecum ismarked by a reduced standard deviation in the ratios of measured greenreflectances and measured blue reflectances over time, and ingestibledevice 65100 may be configured to detect a transition to the cecum basedon determining that the standard deviation of a recent set ofmeasurements is substantially smaller than the standard deviation ofpast measurements taken from the jejunum or ileum.

FIG. 73 is a flowchart of illustrative steps for detecting a transitionfrom a duodenum to a jejunum, which may be used when determining alocation of an ingestible device as it transits through agastrointestinal (GI) tract, in accordance with some embodiments of thedisclosure. Although FIG. 73 may be described in connection with theingestible device 65100 for illustrative purposes, this is not intendedto be limiting, and either portions or the entirety of process 65900described in FIG. 73 may be applied to any device discussed in thisapplication (e.g., the ingestible devices 65100, 65300, and 65400), andany of these ingestible devices may be used to perform one or more partsof the process described in FIG. 73 . Furthermore, the features of FIG.73 may be combined with any other systems, methods or processesdescribed in this application. For example, portions of the processdescribed by the process in FIG. 73 may be integrated into thelocalization process described by FIG. 69 (e.g., as part of 65520-65524of process 65500 (FIG. 69 )). In some embodiments, an ingestible device65100 may perform process 65900 while in the duodenum, or in response todetecting entry to the duodenum. In other embodiments, an ingestibledevice 65100 may perform process 65900 while in the stomach, or inresponse to detecting entry into the GI tract. It is also understoodthat process 65900 may be performed in parallel with any other processdescribed in this disclosure (e.g., process 65600 (FIG. 70 )), which mayenable ingestible device 65100 to detect entry into various portions ofthe GI tract, without necessarily detecting entry into a precedingportion of the GI tract.

For illustrative purposes, FIG. 73 may be discussed in terms ofingestible device 65100 generating and making determinations based on asingle set of reflectance levels generated at a single wavelength by asingle sensing sub-unit (e.g., sensing sub-unit 65126 (FIG. 66 )).However, it is understood that ingestible device 65100 may generatemultiple wavelengths of illumination from multiple different sensingsub-units positioned around the circumference of ingestible device(e.g., multiple sensing sub-units positioned at different locationsbehind window 65114 of ingestible device 65100 (FIG. 65 ), and each ofthe resulting reflectances may be stored as a separate data set.Moreover, each of these sets of reflectance levels may be used to detectmuscle contractions by running multiple versions of process 65900, eachone of which processes data for a different set of reflectancescorresponding to data sets obtained from measurements of differentwavelengths or measurements made by different sensing sub-units.

At 65902, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) retrieves a set of reflectance levels. For example, ingestibledevice 65100 may retrieve a data set of previously recorded reflectancelevels from memory (e.g., from memory circuitry of PCB 65120 (FIG. 66)). Each of the reflectance levels may correspond to reflectancespreviously detected by ingestible device 65100 (e.g., via detector 65122(FIG. 66 )) from illumination generated by ingestible device 65100(e.g., via illuminator 65124 (FIG. 66 )), and may represent a valueindicative of an amount of light detected in a given reflectance.However, it is understood that any suitable frequency of light may beused, such as light in the infrared, visible, or ultraviolet spectrums.In some embodiments, the reflectance levels may correspond toreflectances previously detected by ingestible device 65100 at periodicintervals.

At 904, the ingestible device (e.g., ingestible device 65100, 65300, or65400) includes new measurements of reflectance levels in the data set.For example, ingestible device 65100 may be configured to detect a newreflectance (e.g., transmit illumination and detect the resultingreflectance using sensing sub-unit 65126 (FIG. 66 )) at regularintervals, or with sufficient speed as to detect peristaltic waves. Forexample, ingestible device 65100 may be configured to generateillumination and measure the resulting reflectance once every threeseconds (i.e., potentially minimum rate to detect a 0.17 Hz signal), andpreferably at a higher rate, as fast at 0.1 second or even faster. It isunderstood that the periodic interval between measurements may beadapted as needed based on the species of the subject, and the expectedfrequency of the peristaltic waves to be measured. Every time ingestibledevice 65100 makes a new reflectance level measurement at 65904, the newdata is included to the data set (e.g., a data set stored within memorycircuitry of PCB 65120 (FIG. 66 )).

At 65906, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) obtains a first subset of recent data by applying a slidingwindow filter to the data set. For example, ingestible device 65100 mayretrieve a one-minute worth of data from the data set. If the data setincludes values for reflectances measured every second, this would beapproximately 60 data points worth of data. Any suitable type of windowsize may be used, provided that the size of the window is sufficientlylarge to detect peristaltic waves (e.g., fluctuations on the order of0.05 Hz to 0.33 Hz for healthy human subjects). In some embodiments,ingestible device 65100 may also clean the data, for example, byremoving outliers from the first subset of data obtained through the useof the sliding window filter.

At 65908, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) obtains a second subset of recent data by interpolating thefirst subset of recent data. For example, ingestible device 65100 mayinterpolate the first subset of data in order to generate a secondsubset of data with a sufficient number of data points (e.g., datapoints spaced every 0.5 seconds or greater). In some embodiments, thismay enable ingestible device 65100 to also replace any outlier datapoints that may have been removed as part of applying the window filterat 65906.

At 65910, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) calculates a normalized frequency spectrum from the secondsubset of data. For example, ingestible device 65100 may be configuredto perform a fast Fourier transform to convert the second subset of datafrom a time domain representation into a frequency domainrepresentation. It is understood that depending on the application beingused, and the nature of the subset of data, any number of suitableprocedures (e.g., Fourier transform procedures) may be used to determinea frequency spectrum for the second subset of data. For example, thesampling frequency and size of the second subset of data may be known inadvance, and ingestible device 65100 may be configured to havepre-stored values of a normalized discreet Fourier transform (DFT)matrix, or the rows of the DFT matrix corresponding to the 0.05 Hz to0.33 Hz frequency components of interest, within memory (e.g., memorycircuitry of PCB 65120 (FIG. 66 )). In this case, the ingestible devicemay use matrix multiplication between the DFT matrix and the data set togenerate an appropriate frequency spectrum. An example data set andcorresponding frequency spectrum that may be obtained by the ingestibledevice is discussed in greater detail in relation to FIG. 74 .

At 65912, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) determines whether at least a portion of the normalizedfrequency spectrum is between 00.05 Hz to 0.33 Hz above a thresholdvalue of 0.5 Hz. Peristaltic waves in a healthy human subject occur at arate between 0.05 Hz to 0.33 Hz, and an ingestible device experiencingperistaltic waves (e.g., ingestible device 65400 detecting contractionsin walls 65406 of the jejunum (FIG. 68 )) may detect sinusoidalvariations in the amplitude of detected reflectances levels that followa similar 0.05 Hz to 0.33 Hz frequency. If the ingestible devicedetermines that a portion of the normalized frequency spectrum between0.05 Hz to 0.33 Hz is above a threshold value of 0.5 Hz, thismeasurement may be consistent with peristaltic waves in a healthy humansubject, and process 65900 proceeds to 65914 where ingestible device65100 stores data indicating a muscle contraction was detected.Alternatively, if the ingestible device determines that no portion ofthe normalized frequency spectrum between 0.05 Hz to 0.33 Hz above athreshold value of 0.5, process 65900 proceeds directly to 65904 to makenew measurements and to continue to monitor for new muscle contractions.It is understood that a threshold value other than 0.5 may be used, andthat the exact threshold may depend on the sampling frequency and typeof frequency spectrum used by ingestible device 65100.

At 65914, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) stores data indicating a muscle contraction was detected. Forexample, ingestible device 65100 may store data in memory (e.g., memorycircuitry of PCB 65120 (FIG. 66 )) indicating that a muscle contractionwas detected, and indicating the time that the muscle contraction wasdetected. In some embodiments, ingestible device 65100 may also monitorthe total number of muscle contractions detected, or the number ofmuscle contractions detected in a given time frame. In some embodiments,detecting a particular number of muscle contractions may be consistentwith ingestible device 65100 being within the jejunum (e.g., jejunum65314 (FIG. 67 )) of a healthy human subject. After detecting a musclecontraction, process 65900 proceeds to 65916.

At 65916, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) determines whether a total number of muscle contractionsexceeds a predetermined threshold number. For example, ingestible device65100 may retrieve the total number of muscle contractions detected frommemory (e.g., from memory circuitry of PCB 65120 (FIG. 66 )), andcompare the total number to a threshold value. In some embodiments, thethreshold value may be one, or any number larger than one. The largerthe threshold value, the more muscle contractions need to be detectedbefore ingestible device 65100 stores data indicating that it hasentered the jejunum. In practice, setting the threshold value as threeor higher may prevent the ingestible device from detecting falsepositives (e.g., due to natural movement of the GI tract organs, or dueto movement of the subject). If the total number of contractions exceedsthe predetermined threshold number, process 65900 proceeds to 65918 tostore data indicating detection of a transition from the duodenum to thejejunum. Alternatively, if the total number of contractions does notexceed a predetermined threshold number, process 65900 proceeds to 65904to include new measurements of reflectance levels in the data set. Anexample plot of the muscle contractions detected over time is discussedin greater detail in relation to FIG. 75 .

At 65918, the ingestible device (e.g., ingestible device 65100, 65300,or 65400) stores data indicating detection of a transition from theduodenum to the jejunum. For example, ingestible device 65100 may storedata in memory (e.g., from memory circuitry of PCB 65120 (FIG. 66 ))indicating that the jejunum has been reached. In some embodiments, ifingestible device 65100 is configured to perform all or part of process65900 while in the stomach, ingestible device 65100 may store data at65918 indicating detection of a transition from the stomach directly tothe jejunum (e.g., as a result of transitioning too quickly through theduodenum for the pyloric transition to be detected using process 65600(FIG. 70 )).

In some embodiments, the ingestible device (e.g., ingestible device65100, 65300, or 65400) may be configured to obtain a fluid sample fromthe environment external to a housing of the ingestible device inresponse to identifying a change in the location of the ingestibledevice. For example, ingestible device 65100 may be configured to obtaina fluid sample from the environment external to the housing ofingestible device 65100 (e.g., through the use of optional opening 65116and optional rotating assembly 65118 (FIG. 66 )) in response todetermining that the ingestible device is located within the jejunum(e.g., jejunum 65314 (FIG. 67 )). In some embodiments, ingestible device65100 may also be equipped with appropriate diagnostics to detectcertain medical conditions based on the retrieved fluid sample, such assmall intestinal bacterial overgrowth (SIBO).

In some embodiments, the ingestible device (e.g., ingestible device65100, 65300, or 65400) may be configured to deliver a dispensablesubstance that is pre-stored within the ingestible device from theingestible device into the gastrointestinal tract in response toidentifying the change in the location of the ingestible device. Forexample, ingestible device 65100 may have a dispensable substancepre-stored within the ingestible device 65100 (e.g., within a storagechamber or cavity on optional storage sub-unit 65118-3 (FIG. 66 )), andingestible device 65100 may be configured to dispense the substance intothe gastrointestinal tract (e.g., through the use of optional opening65116 and optional rotating assembly 65118 (FIG. 66 )) when theingestible device 65100 detects that the ingestible device 65100 islocated within the jejunum (e.g., jejunum 65314 (FIG. 67 )). In someembodiments, this may enable ingestible device 65100 to deliversubstances (e.g., therapeutics and medicaments) at targeted locationswithin the GI tract.

In some embodiments, the ingestible device (e.g., ingestible device65100, 65300, or 65400) may be configured to perform an action based onthe total number of detected muscle contractions. For example,ingestible device 65100 may be configured to retrieve data indicative ofthe total number of muscle contractions (e.g., from memory circuitry ofPCB 65120 (FIG. 66 )), and compare that to an expected number of musclecontractions in a healthy individual. In response, the ingestible devicemay either dispense a substance into the gastrointestinal tract (e.g.,through the use of optional opening 65116 and optional rotating assembly65118 (FIG. 66 )), or may obtain a fluid sample from the environmentexternal to the housing of ingestible device 65100 (e.g., through theuse of optional opening 65116 and optional rotating assembly 65118 (FIG.66 )). For instance, ingestible device 65100 may be configured to obtaina sample in response to determining that a number of detected musclecontractions is abnormal, and differs greatly from the expected number.As another example, ingestible device 65100 may be configured to delivera substance into the GI tract (such as a medicament), in response todetermining that the detected muscle contractions are consistent with afunctioning GI tract in a healthy individual.

It will be understood that the steps and descriptions of the flowchartsof this disclosure, including FIG. 73 , are merely illustrative. Any ofthe steps and descriptions of the flowcharts, including FIG. 73 , may bemodified, omitted, rearranged, performed in alternate orders or inparallel, two or more of the steps may be combined, or any additionalsteps may be added, without departing from the scope of the presentdisclosure. For example, the ingestible device 65100 may calculate themean and the standard deviation of multiple data sets in parallel (e.g.,multiple data sets, each one corresponding to a different wavelength ofreflectance or different sensing sub-unit used to detect thereflectance) in order to speed up the overall computation time.Furthermore, it should be noted that the steps and descriptions of FIG.73 may be combined with any other system, device, or method described inthis application, and any of the ingestible devices or systems discussedin this application could be used to perform one or more of the steps inFIG. 73 .

FIG. 6510 is a plot illustrating data collected during an exampleoperation of an ingestible device, which may be used when detecting atransition from a duodenum to a jejunum, in accordance with someembodiments of the disclosure. Diagram 651000 depicts a time domain plot651002 of a data set of reflectance levels measured by an ingestibledevice (e.g., the second subset of data discussed in relation to 65908of FIG. 73 ). In some embodiments, ingestible device 65100 may beconfigured to gather data points at semi-regular intervals approximately0.5 seconds apart. By comparison, diagram 651050 depicts a frequencydomain plot 651004 of the same data set of reflectance levels measuredby an ingestible device (e.g., as a result of ingestible device 65100calculating a frequency spectrum at 65910 of FIG. 73 ). In someembodiments, ingestible device 65100 may be configured to calculate thefrequency spectrum through any convenient means.

In diagram 651050, the range of frequencies 651006 between 0.05 Hz to0.33 Hz may be the range of frequencies that ingestible device 65100searches in order to detect muscle contractions. As shown in diagram651050, there is a strong peak in the frequency domain plot 651004around 0.14 Hz, which is consistent with the frequency of peristalticmotion in a healthy human individual. In this case, an ingestible device65100 analyzing frequency domain plot 651004 may be configured todetermine that the data is consistent with a detected muscle contraction(e.g., using a process similar to 65912 of process 65900 (FIG. 73 )),and may store data (e.g., in memory circuitry of PCB 65120 (FIG. 66 ))indicating that a muscle contraction has been detected. Because themuscle contraction was detected from the one-minute window of dataending at 118 minutes, ingestible device 65100 may also store dataindicating that the muscle contraction was detected at the 118-minutemark (i.e., which may indicate that the ingestible device 65100 wasturned on and ingested by the subject 118 minutes ago).

FIG. 75 is a plot illustrating muscle contractions detected by aningestible device over time, which may be used when determining alocation of an ingestible device as it transits through agastrointestinal (GI) tract, in accordance with some embodiments of thedisclosure. In some embodiments, ingestible device 65100 may beconfigured to detect muscle contractions, and store data indicative ofwhen each muscle contraction is detected (e.g., as part of 65914 ofprocess 65900 (FIG. 73 )). Plot 651100 depicts the detected musclecontractions 651106 over time, with each muscle contraction beingrepresented by a vertical line reaching from “0” to “1” on the y-axis.

At 651102, around the 10-minute mark, ingestible device 65100 firstenters the duodenum (e.g., as determined by ingestible device 65100performing process 65600 (FIG. 70 )). Shortly thereafter, at 651108,ingestible device 65100 begins to detect several muscle contractions1106 in quick succession, which may be indicative of the strongperistaltic waves that form in the jejunum (e.g., jejunum 65314 (FIG. 67)). Later, around 651110, ingestible device 65100 continues to detectintermittent muscle contractions, which may be consistent with aningestible device 65100 within the ileum. Finally at 651104, ingestibledevice 65100 transitions out of the small intestine, and into the cecum.Notably, ingestible device 65100 detects more frequent musclecontractions in the jejunum portion of the small intestine as comparedto the ileum portion of the small intestine, and ingestible device 65100does not measure any muscle contractions after having exited the smallintestine. In some embodiments, ingestible device 65100 may incorporatethis information into a localization process. For example, ingestibledevice 65100 may be configured to detect a transition from a jejunum toan ileum in response to determining that a frequency of detected musclecontractions (e.g., the number of muscle contractions measured in agiven 10-minute window) has fallen below a threshold number. As anotherexample, ingestible device 65100 may be configured to detect atransition from an ileum to a cecum in response to determining that nomuscle contractions have been detected for a threshold period of time.It is understood that these examples are intended to be illustrative,and not limiting, and that measurements of muscle contractions may becombined with any of the other processes, systems, or methods discussedin this disclosure.

FIG. 75 is a flowchart 651200 for certain embodiments for determining atransition of the device from the jejunum to the ileum. It is to benoted that, in general, the jejunum is redder and more vascular than theileum. Moreover, generally, in comparison to the ileum, the jejunum hasa thicker intestine wall with more messentary fat. These differencesbetween the jejunum and the ileum are expected to result in differencesin optical responses in the jejunum relative to the ileum. Optionally,one or more optical signals may be used to investigate the differencesin optical responses. For example, the process can include monitoring achange in optical response in reflected red light, blue light, greenlight, ratio of red light to green light, ratio of red light to bluelight, and/or ratio of green light to blue light. In some embodiments,reflected red light is detected in the process.

Flowchart 651200 represents a single sliding window process. In step651210, the jejenum reference signal is determined based on opticalreflection. Typically, this signal is as the average signal (e.g.,reflected red light) over a period of time since the device wasdetermined to enter the jejenum. The period of time can be, for example,from five minutes to 40 minutes (e.g., from 10 minutes to 30 minutes,from 15 minutes to 25 minutes). In step 651220, the detected signal(e.g., reflected red light) just after the period of time used in step651210 is normalized to the reference signal determined in step 651210.In step 651230, the signal (e.g., reflected red light) is detected. Instep 651240, the mean signal detected based on the single sliding windowis compared to a signal threshold. The signal threshold in step 651240is generally a fraction of the reference signal of the jejenum referencesignal determined in step 651210. For example, the signal threshold canbe from 60% to 90% (e.g., from 70% to 80%) of the jejenum referencesignal. If the mean signal exceeds the signal threshold, then theprocess determines that the device has entered the ileum at step 651250.If the mean signal does not exceed the signal threshold, then theprocess returns to step 651230.

FIG. 77 is a flowchart 651200 for certain embodiments for determining atransition of the device from the jejunum to the ileum using a twosliding window process. In step 651310, the jejenum reference signal isdetermined based on optical reflection. Typically, this signal is as theaverage signal (e.g., reflected red light) over a period of time sincethe device was determined to enter the jejenum. The period of time canbe, for example, from five minutes to 40 minutes (e.g., from 10 minutesto 30 minutes, from 15 minutes to 25 minutes). In step 651320, thedetected signal (e.g., reflected red light) just after the period oftime used in step 651310 is normalized to the reference signaldetermined in step 651310. In step 651330, the signal (e.g., reflectedred light) is detected. In step 651340, the mean difference in thesignal detected based on the two sliding windows is compared to a signalthreshold. The signal threshold in step 651340 is based on whether themean difference in the detected signal exceeds a multiple (e.g., from1.5 times to five times, from two times to four times) of the detectedsignal of the first window. If signal threshold is exceeded, then theprocess determines that the device has entered the ileum at step 651350.If the signal threshold is not exceeded, then the process returns tostep 651330.

FIG. 78 is a flowchart 651400 for a process for certain embodiments fordetermining a transition of the device from the ileum to the cecum. Ingeneral, the process involves detecting changes in the reflected opticalsignal (e.g., red light, blue light, green light, ratio of red light togreen light, ratio of red light to blue light, and/or ratio of greenlight to blue light). In some embodiments, the process includesdetecting changes in the ratio of reflected red light to reflected greenlight, and also detecting changes in the ratio of reflected green lightto reflected blue light. Generally, in the process 651400, the slidingwindow analysis (first and second windows) discussed with respect toprocess 65600 is continued.

Step 651410 includes setting a first threshold in a detected signal,e.g., ratio of detected red light to detected green light, and setting asecond threshold for the coefficient of variation for a detected signal,e.g., the coefficient of variation for the ratio of detected green lightto detected blue light. The first threshold can be set to a fraction(e.g., from 0.5 to 0.9, from 0.6 to 0.8) of the average signal (e.g.,ratio of detected red light to detected green light) in the firstwindow, or a fraction (e.g., from 0.4 to 0.8, from 0.5 to 0.7) of themean difference between the detected signal (e.g., ratio of detected redlight to detected green light) in the two windows. The second thresholdcan be set to 0.1 (e.g., 0.05, 0.02).

Step 651420 includes detecting the signals in the first and secondwindows that are to be used for comparing to the first and secondthresholds.

Step 651430 includes comparing the detected signals to the first andsecond thresholds. If the corresponding value is not below the firstthreshold or the corresponding value is not below the second threshold,then it is determined that the device has not left the ileum and enteredthe cecum, and the process returns to step 651420. If the correspondingvalue is below the first threshold and the corresponding value is belowthe second threshold, then it is determined that the device has left theileum and entered the cecum, and the proceeds to step 651440.

Step 651450 includes determining whether it is the first time that thatthe device was determined to leave the ileum and enter the cecum. If itis the first time that the device was determined to leave the ileum andenter the cecum, then the process proceeds to step 651460. If it is notthe first time that the device has left the ileum and entered the cecum,then the process proceeds to step 651470.

Step 651460 includes setting a reference signal. In this step theoptical signal (e.g., ratio of detected red light to detected greenlight) as a reference signal.

Step 651470 includes determining whether the device may have left thececum and returned to the ileum. The device is determined to have leftthe cecum and returned to the ileum if the corresponding detected signal(e.g., ratio of detected red light to detected green light) isstatistically comparable to the reference signal (determined in step651460) and the coefficient of variation for the corresponding detectedsignal (e.g., ratio of detected green light to detected blue light)exceeds the second threshold. If it is determined that the device mayhave left the cecum and returned to the ileum, the process proceeds tostep 651480.

Step 651480 includes continuing to detect the relevant optical signalsfor a period of time (e.g., at least one minute, from five minutes to 15minutes).

Step 651490 includes determining whether the signals determined in step651480 indicate (using the methodology discussed in step 651470) thatthe device re-entered the ileum. If the signals indicate that the devicere-entered the ileum, the process proceeds to step 651420. If thesignals indicate that the device is in the cecum, the process proceedsto step 651492.

Step 651492 includes continuing to monitor the relevant optical signalsfor a period of time (e.g., at least 30 minutes, at least one hour, atleast two hours).

Step 651494 includes determining whether the signals determined in step651492 indicate (using the methodology discussed in step 651470) thatthe device re-entered the ileum. If the signals indicate that the devicere-entered the ileum, the process proceeds to step 651420. If thesignals indicate that the device is in the cecum, the process proceedsto step 651496.

At step 651496, the process determines that the device is in the cecum.

FIG. 79 is a flowchart 651500 for a process for certain embodiments fordetermining a transition of the device from the cecum to the colon. Ingeneral, the process involves detecting changes in the reflected opticalsignal (e.g., red light, blue light, green light, ratio of red light togreen light, ratio of red light to blue light, and/or ratio of greenlight to blue light). In some embodiments, the process includesdetecting changes in the ratio of reflected red light to reflected greenlight, and also detecting changes in the ratio of reflected blue light.Generally, in the process 651500, the sliding window analysis (first andsecond windows) discussed with respect to process 651400 is continued.

In step 651510, optical signals (e.g., the ratio of reflected red signalto reflected green signal, and reflected blue signal) are collected fora period of time (e.g., at least one minute, at least five minutes, atleast 10 minutes) while the device is in the cecum (e.g., during step651480). The average values for the recorded optical signals (e.g., theratio of reflected red signal to reflected green signal, and reflectedblue signal) establish the cecum reference signals.

In step 651520, the optical signals are detected after it has beendetermined that the device entered the cecum (e.g., at step 651440). Theoptical signals are normalized to the cecum reference signals.

Step 651530 involves determining whether the device has entered thecolon. This includes determining whether any of three different criteriaare satisfied. The first criterion is satisfied if the mean differencein the ratio of a detected optical signal (e.g., ratio of detected redsignal to the detected green) is a multiple greater than one (e.g., 2X,3X, 4X) the standard deviation of the corresponding signal (e.g., ratioof detected red signal to the detected green) in the second window. Thesecond criterion is satisfied if the mean of a detected optical signal(e.g., a ratio of detected red light to detected green light) exceeds agiven value (e.g., exceeds one). The third criterion is satisfied if thecoefficient of variation of an optical signal (e.g., detected bluelight) in the first window exceeds a given value (e.g., exceeds 0.2). Ifany of the three criteria are satisfied, then the process proceeds tostep 651540. Otherwise, none of the three criteria are satisfied, theprocess returns to step 651520.

For illustrative purposes the disclosure focuses primarily on a numberof different example embodiments of an ingestible device, and exampleembodiments of methods for determining a location of an ingestibledevice within a GI tract. However, the possible ingestible devices thatmay be constructed are not limited to these embodiments, and variationsin the shape and design may be made without significantly changing thefunctions and operations of the device. Similarly, the possibleprocedures for determining a location of the ingestible device withinthe GI tract are not limited to the specific procedures and embodimentsdiscussed (e.g., process 65500 (FIG. 69 ), process 65600 (FIG. 70 ),process 65900 (FIG. 73 ), process 651200 (FIG. 76 ), process 651300(FIG. 77 ), process 651400 (FIG. 78 ) and process 651500 (FIG. 79 )).Also, the applications of the ingestible devices described herein arenot limited merely to gathering data, sampling and testing portions ofthe gastrointestinal tract, or delivering medicament. For example, insome embodiments the ingestible device may be adapted to include anumber of chemical, electrical, or optical diagnostics for diagnosing anumber of diseases. Similarly, a number of different sensors formeasuring bodily phenomenon or other physiological qualities may beincluded on the ingestible device. For example, the ingestible devicemay be adapted to measure elevated levels of certain chemical compoundsor impurities in the gastrointestinal tract, or the combination oflocalization, sampling, and appropriate diagnostic and assay techniquesincorporated into a sampling chamber may be particularly well suited todetermine the presence of small intestinal bacterial overgrowth (SIBO).

At least some of the elements of the various embodiments of theingestible device described herein that are implemented via software(e.g., software executed by control circuitry within PCB 65120 (FIG. 66)) may be written in a high-level procedural language such as objectoriented programming, a scripting language or both. Accordingly, theprogram code may be written in C, C⁺⁺ or any other suitable programminglanguage and may comprise modules or classes, as is known to thoseskilled in object oriented programming. Alternatively, or in addition,at least some of the elements of the embodiments of the ingestibledevice described herein that are implemented via software may be writtenin assembly language, machine language or firmware as needed. In eithercase, the language may be a compiled or an interpreted language.

At least some of the program code used to implement the ingestibledevice can be stored on a storage media or on a computer readable mediumthat is readable by a general or special purpose programmable computingdevice having a processor, an operating system and the associatedhardware and software to implement the functionality of at least one ofthe embodiments described herein. The program code, when read by thecomputing device, configures the computing device to operate in a new,specific and predefined manner in order to perform at least one of themethods described herein.

Furthermore, at least some of the programs associated with the systems,devices, and methods of the example embodiments described herein arecapable of being distributed in a computer program product comprising acomputer readable medium that bears computer usable instructions for oneor more processors. The medium may be provided in various forms,including non-transitory forms such as, but not limited to, one or morediskettes, compact discs, tapes, chips, and magnetic and electronicstorage. In some embodiments, the medium may be transitory in naturesuch as, but not limited to, wire-line transmissions, satellitetransmissions, internet transmissions (e.g. downloads), media, digitaland analog signals, and the like. The computer useable instructions mayalso be in various formats, including compiled and non-compiled code.

The techniques described above can be implemented using software forexecution on a computer. For instance, the software forms procedures inone or more computer programs that execute on one or more programmed orprogrammable computer systems (which may be of various architecturessuch as distributed, client/server, or grid) each including at least oneprocessor, at least one data storage system (including volatile andnon-volatile memory and/or storage elements), at least one input deviceor port, and at least one output device or port.

The software may be provided on a storage medium, such as a CD-ROM,readable by a general or special purpose programmable computer ordelivered (encoded in a propagated signal) over a communication mediumof a network to the computer where it is executed. All of the functionsmay be performed on a special purpose computer, or using special-purposehardware, such as coprocessors. The software may be implemented in adistributed manner in which different parts of the computation specifiedby the software are performed by different computers. Each such computerprogram is preferably stored on or downloaded to a storage media ordevice (e.g., solid state memory or media, or magnetic or optical media)readable by a general or special purpose programmable computer, forconfiguring and operating the computer when the storage media or deviceis read by the computer system to perform the procedures describedherein. The inventive system may also be considered to be implemented asa computer-readable storage medium, configured with a computer program,where the storage medium so configured causes a computer system tooperate in a specific and predefined manner to perform the functionsdescribed herein.

For illustrative purposes the examples given herein focus primarily on anumber of different example embodiments of an ingestible device.However, the possible ingestible devices that may be constructed are notlimited to these embodiments, and variations in the general shape anddesign may be made without significantly changing the functions andoperations of the device. For example, some embodiments of theingestible device may feature a sampling chamber substantially towardsthe middle of the device, along with two sets of axial sensingsub-units, each located on substantially opposite ends of the device. Inaddition, the applications of the ingestible device are not limitedmerely to gathering data, sampling and testing portions of thegastrointestinal tract, or delivering medicament. For example, in someembodiments the ingestible device may be adapted to include a number ofchemical, electrical, or optical diagnostics for diagnosing a number ofdiseases. Similarly, a number of different sensors for measuring bodilyphenomenon or other physiological qualities may be included on theingestible device. For example, the ingestible device may be adapted tomeasure elevated levels of certain analytes, chemical compounds orimpurities in the gastrointestinal tract, or the combination oflocalization, sampling, and appropriate diagnostic and assay techniquesincorporated into a sampling chamber may be particularly well suited todetermine the presence of small intestinal bacterial overgrowth (SIBO).It is also noted that although embodiments described herein focus on aningestible device in the GI tract, such ingestible device described inFIGS. 1-64 may be used for delivering substances including medicamentsand therapeutics in other parts of the body, such as but not limited tothe female reproductive tract, and/or the like.

The various embodiments of systems, processes and apparatuses have beendescribed herein by way of example only. It is contemplated that thefeatures and limitations described in any one embodiment may be appliedto any other embodiment herein, and flowcharts or examples relating toone embodiment may be combined with any other embodiment in a suitablemanner, done in different orders, or done in parallel. It should benoted, the systems and/or methods described above may be applied to, orused in accordance with, other systems and/or methods. Variousmodifications and variations may be made to these example embodimentswithout departing from the spirit and scope of the embodiments, which islimited only by the appended embodiments. The appended embodimentsshould be given the broadest interpretation consistent with thedescription as a whole.

Implementations of the subject matter and the operations described inthis specification can be implemented by digital electronic circuitry,or via computer software, firmware, or hardware, including thestructures disclosed in this specification and their structuralequivalents, or in combinations of one or more of them. Implementationsof the subject matter described in this specification can be implementedas one or more computer programs, i.e., one or more modules of computerprogram instructions, encoded on computer storage medium for executionby, or to control the operation of, data processing apparatus.

A computer storage medium can be, or be included in, a computer-readablestorage device, a computer-readable storage substrate, a random orserial access memory array or device, or a combination of one or more ofthem. Moreover, while a computer storage medium is not a propagatedsignal, a computer storage medium can be a source or destination ofcomputer program instructions encoded in an artificially generatedpropagated signal. The computer storage medium can also be, or beincluded in, one or more separate physical components or media (e.g.,multiple CDs, discs, or other storage devices).

The operations described in this specification can be implemented asoperations performed by a data processing apparatus on data stored onone or more computer-readable storage devices or received from othersources.

The term “data processing apparatus” encompasses all kinds of apparatus,devices, and machines for processing data, including by way of example aprogrammable processor, a computer, a system on a chip, or multipleones, or combinations, of the foregoing. The apparatus can includespecial purpose logic circuitry, e.g., an FPGA (field programmable gatearray) or an ASIC (application specific integrated circuit). Theapparatus can also include, in addition to hardware, code that createsan execution environment for the computer program in question, e.g.,code that constitutes processor firmware, a protocol stack, a databasemanagement system, an operating system, a cross-platform runtimeenvironment, a virtual machine, or a combination of one or more of them.The apparatus and execution environment can realize various differentcomputing model infrastructures, such as web services, distributedcomputing and grid computing infrastructures.

A computer program (also known as a program, software, softwareapplication, script, or code) can be written in any form of programminglanguage, including compiled or interpreted languages, declarative orprocedural languages, and it can be deployed in any form, including as astand-alone program or as a module, component, subroutine, object, orother unit suitable for use in a computing environment. A computerprogram may, but need not, correspond to a file in a file system. Aprogram can be stored in a portion of a file that holds other programsor data (e.g., one or more scripts stored in a markup languagedocument), in a single file dedicated to the program in question, or inmultiple coordinated files (e.g., files that store one or more modules,sub programs, or portions of code). A computer program can be deployedto be executed on one computer or on multiple computers that are locatedat one site or distributed across multiple sites and interconnected by acommunication network.

The processes and logic flows described in this specification can beperformed by one or more programmable processors executing one or morecomputer programs to perform actions by operating on input data andgenerating output. The processes and logic flows can also be performedby, and apparatus can also be implemented as, special purpose logiccircuitry, e.g., a FPGA (field programmable gate array) or an ASIC(application specific integrated circuit).

Processors suitable for the execution of a computer program include, byway of example, both general and special purpose microprocessors, andany one or more processors of any kind of digital computer. Generally, aprocessor will receive instructions and data from a read only memory ora random access memory or both. The essential elements of a computer area processor for performing actions in accordance with instructions andone or more memory devices for storing instructions and data. Generally,a computer will also include, or be operatively coupled to receive datafrom or transfer data to, or both, one or more mass storage devices forstoring data, e.g., magnetic, magneto optical discs, or optical discs.However, a computer need not have such devices. Moreover, a computer canbe embedded in another device, e.g., a mobile telephone, a personaldigital assistant (PDA), a mobile audio or video player, a game console,a Global Positioning System (GPS) receiver, or a portable storage device(e.g., a universal serial bus (USB) flash drive), to name just a few.Devices suitable for storing computer program instructions and datainclude all forms of non-volatile memory, media and memory devices,including by way of example semiconductor memory devices, e.g., EPROM,EEPROM, and flash memory devices; magnetic discs, e.g., internal harddiscs or removable discs; magneto optical discs; and CD ROM and DVD-ROMdiscs. The processor and the memory can be supplemented by, orincorporated in, special purpose logic circuitry.

To provide for interaction with a user, implementations of the subjectmatter described in this specification can be implemented on a computerhaving a display device, e.g., a CRT (cathode ray tube) or LCD (liquidcrystal display) monitor, for displaying information to the user and akeyboard and a pointing device, e.g., a mouse or a trackball, by whichthe user can provide input to the computer. Other kinds of devices canbe used to provide for interaction with a user as well; for example,feedback provided to the user can be any form of sensory feedback, e.g.,visual feedback, auditory feedback, or tactile feedback; and input fromthe user can be received in any form, including acoustic, speech, ortactile input. In addition, a computer can interact with a user bysending documents to and receiving documents from a device that is usedby the user; for example, by sending web pages to a web browser on auser’s user device in response to requests received from the webbrowser.

Implementations of the subject matter described in this specificationcan be implemented in a computing system that includes a back endcomponent, e.g., as a data server, or that includes a middlewarecomponent, e.g., an application server, or that includes a front endcomponent, e.g., a user computer having a graphical display or a Webbrowser through which a user can interact with an implementation of thesubject matter described in this specification, or any combination ofone or more such back end, middleware, or front end components. Thecomponents of the system can be interconnected by any form or medium ofdigital data communication, e.g., a communication network. Examples ofcommunication networks include a local area network (“LAN”) and a widearea network (“WAN”), an inter-network (e.g., the Internet), andpeer-to-peer networks (e.g., ad hoc peer-to-peer networks).

The computing system can include users and servers. A user and serverare generally remote from each other and typically interact through acommunication network. The relationship of user and server arises byvirtue of computer programs running on the respective computers andhaving a user-server relationship to each other. In someimplementations, a server transmits data (e.g., an HTML page) to a userdevice (e.g., for purposes of displaying data to and receiving userinput from a user interacting with the user device). Data generated atthe user device (e.g., a result of the user interaction) can be receivedfrom the user device at the server.

While this specification contains many specific implementation details,these should not be construed as limitations on the scope of anyinventions or of what may be claimed, but rather as descriptions offeatures specific to particular implementations of particularinventions. Certain features that are described in this specification inthe context of separate implementations can also be implemented incombination in a single implementation. Conversely, various featuresthat are described in the context of a single implementation can also beimplemented in multiple implementations separately or in any suitablesub combination. Moreover, although features may be described above asacting in certain combinations and even initially claimed as such, oneor more features from a claimed combination can in some cases be excisedfrom the combination, and the claimed combination may be directed to asub combination or variation of a sub combination.

For the purpose of this disclosure, the term “coupled” means the joiningof two members directly or indirectly to one another. Such joining maybe stationary or moveable in nature. Such joining may be achieved withthe two members or the two members and any additional intermediatemembers being integrally formed as a single unitary body with oneanother or with the two members or the two members and any additionalintermediate members being attached to one another. Such joining may bepermanent in nature or may be removable or releasable in nature.

It should be noted that the orientation of various elements may differaccording to other exemplary implementations, and that such variationsare intended to be encompassed by the present disclosure. It isrecognized that features of the disclosed implementations can beincorporated into other disclosed implementations.

EXAMPLES Experiment 1

An ingestible medical device according to the disclosure (“TLC1”) wastested on 20 subjects to investigate its localization ability. TLC1 wasa biocompatible polycarbonate capsule that contained a power supply,electronics and software. An onboard software algorithm used time,temperature and reflected light spectral data to determine the locationof the capsule as it traveled the GI tract. The capsule is 0.51 × 1.22inches which is larger than a vitamin pill which is 0.4 × 0.85 inches.The subjects fasted overnight before participating in the study.Computerized tomography (“CT”) were used as a basis for determining theaccuracy of the localization data collected with TLC1. One of the 20subjects did not follow the fasting rule. CT data was lacking foranother one of the 20 subjects. Thus, these two subjects were excludedfrom further analysis. TLC1 sampled RGB data (radially transmitted)every 15 seconds for the first 14 hours after it entered the subject’sstomach, and then samples every five minutes after that until batterydies. TLC1 did not start to record optical data until it reached thesubject’s stomach. Thus, there was no RGB-based data for themouth-esophagus transition for any of the subjects.

In addition, a PillCam® SB (Given Imaging) device was tested on 57subjects. The subjects fasted overnight before joining the study.PillCam videos were recorded within each subject. The sampling frequencyof PillCam is velocity dependent. The faster PillCam travels, the fasterit would sample data. Each video is about seven to eight hours long,starting from when the capsule was administrated into the subject’smouth. RGB optical data were recorded in a table. A physician providednotes on where stomach-duodenum transition and ileum-cecum transitionoccurred in each video. Computerized tomography (“CT”) was used as abasis for determining the accuracy of the localization data collectedwith PillCam.

Esophagus-Stomach Transition

For TLC1, it was assumed that this transition occurred one minute afterthe patient ingested the device. For PillCam, the algorithm was asfollows:

-   1. Start mouth-esophagus transition detection after capsule is    activated/administrated-   2. Check whether Green < 102.3 and Blue < 94.6    -   a. If yes, mark as mouth-esophagus transition    -   b. If no, continue to scan the data-   3. After detecting mouth-esophagus transition, continue to monitor    Green and Blue signals for another 30 seconds, in case of location    reversal    -   a. If either Green > 110.1 or Blue > 105.5, mark it as        mouth-esophagus location reversal    -   b. Reset the mouth-esophagus flag and loop through step 2 and 3        until the confirmed mouth-esophagus transition detected-   4. Add one minute to the confirmed mouth-esophagus transition and    mark it as esophagus-stomach transition

For one of the PillCam subjects, there was not a clear cut differencebetween the esophagus and stomach, so this subject was excluded fromfuture analysis of stomach localization. Among the 56 valid subjects, 54of them have correct esophagus-stomach transition localization. Thetotal agreement is 54/56=96%. Each of the two failed cases had prolongedesophageal of greater than one minute. Thus, adding one minute tomouth-esophagus transition was not enough to cover the transition inesophagus for these two subjects.

Stomach-Duodenum

For both TLC1 and PillCam, a sliding window analysis was used. Thealgorithm used a dumbbell shape two-sliding-window approach with a twominute gap between the front (first) and back (second) windows. The twominute gap was designed, at least in part, to skip the rapid transitionfrom stomach to small intestine and capture the small intestine signalafter capsule settles down in small intestine. The algorithm was asfollows:

-   1. Start to check for stomach-duodenum transition after capsule    enters stomach-   2. Setup the two windows (front and back)    -   a. Time length of each window: 3 minutes for TLC1; 30 seconds        for PillCam    -   b. Time gap between two windows: 2 minutes for both devices    -   c. Window sliding step size: 0.5 minute for both devices-   3. Compare signals in the two sliding windows    -   a. If difference in mean is higher than 3 times the standard        deviation of Green/Blue signal in the back window        -   i. If this is the first time ever, record the mean and            standard deviation of signals in the back window as stomach            reference        -   ii. If mean signal in the front window is higher than            stomach reference signal by a certain threshold (0.3 for            TLC1 and 0.18 for PillCam), mark this as a possible            stomach-duodenum transition    -   b. If a possible pyloric transition is detected, continue to        scan for another 10 minutes in case of false positive flag        -   i. If within this 10 minutes, location reversal is detected,            the previous pyloric transition flag is a false positive            flag. Clear the flag and continue to check        -   ii. If no location reversal has been identified within 10            minutes following the possible pyloric transition flag, mark            it as a confirmed pyloric transition    -   c. Continue monitoring Green/Blue data for another 2 hours after        the confirmed pyloric transition, in case of location reversal        -   i. If a location reversal is identified, flag the timestamp            when reversal happened and then repeat steps a-c to look for            the next pyloric transition        -   ii. If the capsule has not gone back to stomach 2 hours            after previously confirmed pyloric transition, stops            location reversal monitoring and assume the capsule would            stay in intestinal area

For TLC1, one of the 18 subjects had too few samples (<3 minutes) takenin the stomach due to the delayed esophagus-stomach transitionidentification by previously developed localization algorithm. Thus,this subject was excluded from the stomach-duodenum transition algorithmtest. For the rest of the TLC1 subjects, CT images confirmed that thedetected pyloric transitions for all the subjects were located somewherebetween stomach and jejunum. Two out of the 17 subjects showed that thecapsule went back to stomach after first the first stomach-duodenumtransition. The total agreement between the TLC1 algorithm detection andCT scans was 17/17 = 100%.

For one of the PillCam subjects, the capsule stayed in the subject’sstomach all the time before the video ended. For another two of thePillCam subjects, too few samples were taken in the stomach to run thelocalization algorithm. These three PillCam subjects were excluded fromthe stomach-duodenum transition localization algorithm performance test.The performance summary of pyloric transition localization algorithm forPillCam was as follows:

-   1. Good cases (48 subjects):    -   a. For 25 subjects, our detection matches exactly with the        physician’s notes    -   b. For 19 subjects, the difference between the two detections is        less than five minutes    -   c. For four subjects, the difference between the two detections        is less than 10 minutes        -   (The full transition could take up to 10 minutes before the            G/B signal settled)-   2. Failed cases (6 subjects):    -   a. Four subjects had high standard deviation of Green/Blue        signal in the stomach    -   b. One subject had bile in the stomach, which greatly affected        Green/Blue in stomach    -   c. One subject had no Green/Blue change at pyloric transition

The total agreement for the PillCam stomach-duodenum transitionlocalization algorithm detection and physician’s notes was 48/54 = 89%.

Duodenum-Jejenum Transition

For TLC1, it was assumed that the device left the duodenum and enteredthe jejenum three minutes after it was determined that the deviceentered the duodenum. Of the 17 subjects noted above with respect to theTLC1 investigation of the stomach-duodenum transition, 16 of thesubjects mentioned had CT images that confirmed that theduodenum-jejenum transition was located somewhere between stomach andjejunum. One of the 17 subjects had a prolonged transit time induodenum. The total agreement between algorithm detection and CT scanswas 16/17 = 94%.

For PillCam, the duodenum-jejenum transition was not determined.

Jejenum-Ileum Transition

It is to be noted that the jejunum is redder and more vascular thanileum, and that the jejenum has a thicker intestine wall with moremesentery fat. These differences can cause various optical responsesbetween jejunum and ileum, particularly for the reflected red lightsignal. For both TLC1 and PillCam, two different approaches wereexplored to track the change of red signal at the jejunum-ileumtransition. The first approach was a single-sliding-window analysis,where the window is 10 minutes long, and the mean signal was comparedwith a threshold value while the window was moving along. The secondapproach was a two-sliding-window analysis, where each window was 10minutes long with a 20 minute spacing between the two windows. Thealgorithm for the jejunum-ileum transition localization was as follows:

-   1. Obtain 20 minutes of Red signal after the duodenum-jejenum    transition, average the data and record it as the jejunum reference    signal-   2. Start to check the jejunum-ileum transition 20 minutes after the    device enters the jejunum    -   a. Normalize the newly received data by the jejunum reference        signal    -   b. Two approaches:        -   i. Single-sliding-window analysis            -   Set the transition flag if the mean of reflected red                signal is less than 0.8        -   ii. Two-sliding-window analysis:            -   Set the transition flag if the mean difference in                reflected red is higher than 2X the standard deviation                of the reflected red signal in the front window

For TLC1, 16 of the 18 subjects had CT images that confirmed that thedetected jejunum-ileum transition fell between jejunum and cecum. Thetotal agreement between algorithm and CT scans was 16/18 = 89%. This wastrue for both the single-sliding-window and double-sliding-windowapproaches, and the same two subjects failed in both approaches.

The performance summary of the jejunum-ileum transition detection forPillCam is listed below:

-   1. Single-sliding-window analysis:    -   a. 11 cases having jejunum-ileum transition detected somewhere        between jejunum and cecum    -   b. 24 cases having jejunum-ileum transition detected after cecum    -   c. 19 cases having no jejunum-ileum transition detected    -   d. Total agreement: 11/54 = 20%-   2. Two-sliding-window analysis:    -   a. 30 cases having jejunum-ileum transition detected somewhere        between jejunum and cecum    -   b. 24 cases having jejunum-ileum transition detected after cecum    -   c. Total agreement: 30/54 = 56%

Ileum-Cecum Transition

Data demonstrated that, for TLC1, mean signal of reflected red/greenprovided the most statistical difference before and after theileum-cecum transition. Data also demonstrated that, for TLC1, thecoefficient of variation of reflected green/blue provided the moststatistical contrast at ileum-cecum transition. The analysis based onPillCam videos showed very similar statistical trends to those resultsobtained with TLC1 device. Thus, the algorithm utilized changes in meanvalue of reflected red/green and the coefficient of variation ofreflected green/blue. The algorithm was as follows:

-   1. Start to monitor ileum-cecum transition after the capsule enters    the stomach-   2. Setup the two windows (front (first) and back (second))    -   a. Use a five minute time length for each window    -   b. Use a 10 minute gap between the two windows    -   c. Use a one minute window sliding step size-   3. Compare signals in the two sliding windows    -   a. Set ileum-cecum transition flag if        -   i. Reflected red/green has a significant change or is lower            than a threshold        -   ii. Coefficient of variation of reflected green/blue is            lower than a threshold    -   b. If this is the first ileum-cecum transition detected, record        average reflected red/green signal in small intestine as small        intestine reference signal    -   c. Mark location reversal (i.e. capsule returns to terminal        ileum) if        -   i. Reflected red/green is statistically comparable with            small intestine reference signal        -   ii. Coefficient of variation of reflected green/blue is            higher than a threshold    -   d. If a possible ileum-cecum transition is detected, continue to        scan for another 10 minutes for TLC1 (15 minutes for PillCam) in        case of false positive flag        -   i. If within this time frame (10 minutes for TLC1, 15            minutes for PillCam), location reversal is detected, the            previous ileum-cecum transition flag is a false positive            flag. Clear the flag and continue to check        -   ii. If no location reversal has been identified within this            time frame (10 minutes for TLC1, 15 minutes for PillCam)            following the possible ileum-cecum transition flag, mark it            as a confirmed ileum-cecum transition    -   e. Continue monitoring data for another 2 hours after the        confirmed ileum-cecum transition, in case of location reversal        -   i. If a location reversal is identified, flag the timestamp            when reversal happened and then repeat steps a-d to look for            the next ileum-cecum transition        -   ii. If the capsule has not gone back to small intestine 2            hours after previously confirmed ileum-cecum transition,            stop location reversal monitoring and assume the capsule            would stay in large intestinal area

The flag setting and location reversal criteria particularly designedfor TLC1 device were as follows:

-   1. Set ileum-cecum transition flag if    -   a. The average reflected red/Green in the front window is less        than 0.7 or mean difference between the two windows is higher        than 0.6    -   b. And the coefficient of variation of reflected green/blue is        less than 0.02-   2. Define as location reversal if    -   a. The average reflected red/green in the front window is higher        than small intestine reference signal    -   b. And the coefficient of variation of reflected green/blue is        higher than 0.086

For TLC1, 16 of the 18 subjects had CT images that confirmed that thedetected ileum-cecum transition fell between terminal ileum and colon.The total agreement between algorithm and CT scans was 16/18 = 89%.Regarding those two subject where the ileum-cecum transitionlocalization algorithm failed, for one subject the ileum-cecumtransition was detected while TLC1 was still in the subject’s terminalileum, and for the other subject the ileum-cecum transition was detectedwhen the device was in the colon.

Among the 57 available PillCam endoscopy videos, for three subjects theendoscopy video ended before PillCam reached cecum, and another twosubjects had only very limited video data (less than five minutes) inthe large intestine. These five subjects were excluded from ileum-cecumtransition localization algorithm performance test. The performancesummary of ileum-cecum transition detection for PillCam is listed below:

-   1. Good cases (39 subjects):    -   a. For 31 subjects, the difference between the PillCam detection        and the physician’s notes was less than five minutes    -   b. For 3 subjects, the difference between the PillCam detection        and the physician’s notes was less than 10 minutes    -   c. For 5 subjects, the difference between the PillCam detection        and the physician’s notes was less than 20 minutes (the full        transition can take up to 20 minutes before the signal settles)-   2. Marginal/bad cases (13 subjects):    -   a. Marginal cases (9 subjects)        -   i. The PillCam ileum-cecum transition detection appeared in            the terminal ileum or colon, but the difference between the            two detections was within one hour    -   b. Failed cases (4 subjects)        -   i. Reasons of failure:            -   1. The signal already stabilized in the terminal ileum            -   2. The signal was highly variable from the entrance to                exit            -   3. There was no statistically significant change in                reflected red/green at ileum-cecum transition

The total agreement between ileocecal transition localization algorithmdetection and the physician’s notes is 39/52 = 75% if considering goodcases only. Total agreement including possibly acceptable cases is 48/52= 92.3%.

Cecum-Colon Transition

Data demonstrated that, for TLC1, mean signal of reflected red/greenprovided the most statistical difference before and after thececum-colon transition. Data also demonstrated that, for TLC1, thecoefficient of variation of reflected blue light provided the moststatistical contrast at cecum-colon transition. The same signals wereused for PillCam. The cecum-colon transition localization algorithm wasas follows:

-   1. Obtain 10 minutes of reflected red/green and reflected blue    signals after ileum-cecum transition, average the data and record it    as the cecum reference signals-   2. Start to check cecum-colon transition after capsule enters cecum    (The cecum-colon transition algorithm is dependent on the    ileum-cecum transition flag)    -   a. Normalize the newly received data by the cecum reference        signals    -   b. Two-sliding-window analysis:        -   i. Use two adjacent 10 minute windows        -   ii. Set the transition flag if any of the following criteria            were met            -   The mean difference in reflected red/green was more than                4X the standard deviation of reflected red/green in the                back (second) window            -   The mean of reflected red/green in the front (first)                window was higher than 1.03            -   The coefficient of variation of reflected blue signal in                the front (first) window was greater than 0.23

The threshold values above were chosen based on a statistical analysisof data taken by TLC1.

For TLC1, 15 of the 18 subjects had the cecum-colon transition detectedsomewhere between cecum and colon. One of the subjects had thececum-colon transition detected while TLC1 was still in cecum. The othertwo subjects had both wrong ileum-cecum transition detection and wrongcecum-colon transition detection. The total agreement between algorithmand CT scans was 15/18 = 83%.

For PillCam, for three subjects the endoscopy video ended before PillCamreached cecum, and for another two subjects there was very limited videodata (less than five minutes) in the large intestine. These fivesubjects were excluded from cecum-colon transition localizationalgorithm performance test. The performance summary of cecum-colontransition detection for PillCam is listed below:

-   1. 27 cases had the cecum-colon transition detected somewhere    between the cecum and the colon-   2. one case had the cecum-colon transition detected in the ileum-   3. 24 cases had no cecum-colon transition localized

The total agreement: 27/52 = 52%.

The following table summarizes the localization accuracy results.

Transition TLC1 PillCam Stomach-Duodenum 100% (17/17) 89% (48/54)Duodenum-Jejenum 94% (16/17) N/A Ileum-Cecum 89% (16/18) 75% (39/52)Ileum-terminal ileum/cecum/colon 100 % (18/18) 92% (48/52)

Experiment 2

Experiments were run to evaluate the effects that bellows material wouldhave on the function of a drug used as the dispensable substance. Theexperiments also evaluated the effects on drug function due to shelflife in the bellows.

The drug Exemptia (adalimumab) was loaded into simulated device jigscontaining either tapered silicone bellows or smooth PVC bellows andallowed to incubate for 4, 24, or 336 hours at room temperature whileprotected from light. FIG. 80 illustrates the tapered silicone bellows,and FIG. 81 illustrates the tapered silicone bellows in the simulateddevice jig. FIG. 82 illustrates the smooth PVC bellows, and FIG. 83illustrates the smooth PVC in the simulated device jig.

The drug was subsequently extracted using the respective dispensingsystems and tested by a competitive inhibition assay. The test methodhas been developed from the literature (Velayudhan et al.,“Demonstration of functional similarity of proposed biosimilar ABP501 toadalimumab” BioDrugs 30:339-351 (2016) and Barbeauet et al.,“Application Note: Screening for inhibitors of TNFα/s TNFR1 Bindingusing AlphaScreen™ Technology”. PerkinElmer Technical Note ASC-016.(2002)), as well as pre-testing development work using control drug andexperiments using the provided AlphaLISA test kits. FIG. 84 demonstratesthe principle of the competition assay performed in the experiment.

The bellows were loaded as follows: aseptically wiped the dispensingport of the simulated capsule jig with 70% ethanol; allowed to air dryfor one minute; used an Exemptia delivery syringe to load each set ofbellows with 200 µL of drug; took a photo of the loaded device; gentlyrotated the device such that the drug is allowed to come in contact withall bellows surfaces; protected the bellows from light; and incubate atroom temperature for the predetermined time period to allow full contactof the drug with all bellows surfaces.

The drug was extracted as follows: after completion of the incubationperiod; the device jig was inverted such that the dispensing port waspositioned over a sterile collection microfuge tube and petri dishbelow; five cubic centimeters of air was drawn into an appropriatesyringe; the lure lock was attached to the device jig; the syringe wasused to gently apply positive pressure to the bellow with air such thatthe drug was recovered in the collection microfuge tube; where possible,a video of drug dispensing was taken; samples were collected from eachbellows type; a control drug sample was collected by directly dispensing200 µL of drug from the commercial dispensing syringe into a sterilemicrofuge tube; the control drug-free sample was collected by directlydispensing 200 µL of PBS using a sterile pipette into a sterilemicrofuge tube; the collected drug was protected from light; and thedrug was diluted over the following dilution range (250, 125, 25, 2.5,0.25, 0.025, 0.0125, 0.0025 µg) in sterile PBS to determine the IC50range of the drug.

To determine any effects storage conditions may have on drug efficacy inthe device, the drug (stored either in the syringe, silicon bellows, PVCbellows) was stored at room temperature while protected from light for24 hours and 72 hours. Samples were then extracted and the steps in thepreceding paragraph were repeated.

The AlphaLISA (LOCI™) test method was used. Human TNFα standard dilutionranges were prepared as described in Table 4.

TABLE 4 Tube Vol. of human TNFα (µL) Vol. of diluent (µL) * [human TNFα]in standard curve (g/mL in 5 µL) (pg/mL in 5 μL A 10 µL of reconstitutedhuman TNFα 90 1E-07 100 000 B 60 µL of tube A 140 3E-08 30 000 C 60 µLof tube B 120 1E-08 10 000 D 60 µL of tube C 140 3E-09 3 000 E 60 µL oftube D 120 1E-09 1 000 F 60 µL of tube E 140 3E-10 300 G 60 µL of tube F120 1E-10 100 H 60 µL of tube G 140 3E-11 30 I 60 µL of tube H 120 1E-1110 J 60 µL of tube I 140 3E-12 3 K 60 µL of tube J 120 1E-12 1 L 60 µLof tube K 140 3E-13 0.3 M ** (background) 0 100 0 0 N ** (background) 0100 0 0 O ** (background) 0 100 0 0 P ** (background) 0 100 0 0

The test was performed as follows: the above standard dilution rangeswere in a separate 96 well plate; to ensure consistent mixing, sampleswere mixed up and down gently with a pipette five times; a 384 well testplate was prepared according to the test layout diagram depicted Table5; five microliters of 10,000 pg/mL TNFα standard from the previouslymade dilution plate was added to each corresponding concentration asshown in Table 5; five microliters of recovered drug (directly from thecommercial syringe (A), from the silicone bellows (B Si), from the PVCbellows (B PVC), or from the PBS control (C)) was added into thecorresponding wells described in Table 5; the test plate was incubatedfor one hour at room temperature while protected from light; 10microliters of acceptor beads were added to each previously accessedwell; the wells were incubated for 30 minutes at room temperature whileprotected form light; 10 µL of biotinylated antibody was added to eachpreviously accessed well; the wells were incubated for 15 minutes atroom temperature, while protected from light; the room lights weredarkened and 25 microliters of SA donor beads were added to eachpreviously accessed well; the wells were incubated for 30 minutes atroom temperature while protected form light; the plate was read in AlphaMode; and the results were recorded. Upon addition of reagent(s) in thevarious steps, each well was pipetted up and down three times to achievegood mixing.

TABLE 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 ASTD2 STD10 250 250 250 250 250 250 250 250 250 250 250 250 250 250 250250 250 250 250 250 1.00E+05 10 A A A A A B Si B Si B Si B Si B Si B PVCB PVC B PVC B PVC B PVC C C C C C B C STD3 STD11 125 125 125 125 125 125125 125 125 125 125 125 125 125 125 125 125 125 125 125 30000 3 A A A AA B Si B Si B Si B Si B Si B PVC B PVC B PVC B PVC B PVC C C C C C D ESTD4 STD12 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 2510000 1 A A A A A B Si B Si B Si B Si B Si B PVC B PVC B PVC B PVC B PVCC C C C C F G STD5 STD13 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.52.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 3000 0.333 A A A A A B Si B Si B Si B SiB Si B PVC B PVC B PVC B PVC B PVC C C C C C H I STD6 Blank 0.25 0.250.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.250.25 0.25 0.25 0.25 1000 0 A A A A A B Si B Si B Si B Si B Si B PVC BPVC B PVC B PVC B PVC C C C C C J K STD7 Blank 0.025 0.025 0.025 0.0250.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.0250.025 0.025 0.025 0.025 300 0 A A A A A B Si B Si B Si B Si B Si B PVC BPVC B PVC B PVC B PVC C C C C C L M STD8 Blank 0.013 0.013 0.013 0.0130.013 0.013 0.013 0.013 0.013 0.013 0.013 0.013 0.013 0.013 0.013 0.0130.013 0.013 0.013 0.013 100 0 A A A A A B Si B Si B Si B Si Si B PVC BPVC B PVC B PVC B PVC C C C C C N O STD9 Blank 0.003 0.003 0.003 0.0030.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.0030.003 0.003 0.003 0.003 30 0 A A A A A B Si B Si B Si B Si B Si B PVC BPVC B PVC B PVC B PVC C C C C C P

The data are shown in FIGS. 85-87 . The data demonstrate that thebellows do not negatively impact the drug function after shelf lives of4, 24 hours, or 336 hours. IC50 values of the drug dispensed from thebellows were comparable to the IC50 values of the standard dispensationmethod (Table 6). A slight right shift was noted in the bellows curvesafter 24 hours (FIG. 86 ), but this shift was well within the error barsof the curves. Tables 7-9 represent data of FIGS. 85-87 , respectively.Of note, when comparing mean (n=5) RFU data between test articles overthe concentration ranges significant differences (p<0.05) werediscerned. However, these significant differences did not favor eithertest article over time, suggesting that they were not related to theperformance of the material in response to the drug (FIGS. 85-87 ).

TABLE 6 Needle control (A) Silicone Bellows (B) PVC Bellows (C) 4 Hours0.0174 0.0169 0.0172 24 Hours 0.0180 0.0180 0.0180 336 Hours 0.01440.0159 0.0163

TABLE 7 Statistics (Student’s T-test, 2 tailed, non-pair-wise, forsignificance p<0.05) Drug (micrograms) Needle control (A) vs. Silicone(B) Needle control (A) vs. PVC Silicone vs. PVC 0.0001 0.911 0.008*0.268 0.0025 0.138 0.390 0.822 0.0125 0.122 0.118 0.771 0.025 0.1430.465 0.020* 0.25 0.591 0.984 0.350 2.5 0.243 0.124 0.169 125 0.8670.688 0.182 250 0.681 0.184 0.108 *p<0.5 data set

TABLE 8 Statistics (Student’s T-test, 2 tailed, non-pair-wise, forsignificance p<0.05) Drug (micrograms) Needle control (A) vs. Silicone(B) Needle control (A) vs. PVC Silicone vs. PVC 0.0001 0.132 0.038*0.292 0.0025 0.003* 0.076 0.575 0.0125 0.161 0.022* 0.783 0.025 0.0580.078 0.538 0.25 0.974 0.384 0.198 2.5 0.714 0.080 0.017* 125 0.8730.731 0.269 250 0.798 0.956 0.903 *p<0.5 data set

TABLE 9 Statistics (Student’s T-test, 2 tailed, non-pair-wise, forsignificance p<0.05) Drug (micrograms) Needle control (A) vs. Silicone(B) Needle control (A) vs. PVC Silicone vs. PVC 0.0001 0.8584490.036847* 0.026444* 0.0025 0.087379 0.280302 0.046767* 0.0125 0.4692820.057232 0.117194 0.025 0.02758* 0.078234 0.373419 0.25 0.4115480.258928 0.400498 2.5 0.368959 0.156574 0.006719* 125 0.948649 0.2467020.463735 250 0.485046 0.128993 0.705543 *p<0.5 data set

Experiment 3

Tests were conducted to determine whether certain pressures used todeliver a drug with an ingestible device disclosed herein would resultin physical damage to the drug.

A target analyte (Novolog) was loaded into a jet device including apiston with a release mechanism. On the back side of the piston,pressure was provided by a hand pump, and the release mechanism wasreleased to release Novolog. The end fastener was screwed on to securethe nozzle insert and seal the chamber. The jet device was operated at atarget pressure to dispense target analyte into a polypropylene tube forcollection and analysis. For the minimum pressure test, the jet wasoperated manually by slowly pushing the piston forward to dispense thetarget analyte. For the maximum pressure test, 150 pounds per squareinch (psi) were applied to the jet device, and the target analyte wascarefully dispensed into a collection tube. For a positive control, theanalyte was dispensed using a standard syringe, and a negative controlwas prepared by running the analyte through a series of boiling andfreeze thaw cycles to cause intentional physical damage. Drug efficacywas detected by running the collected samples in a commercial ELISA kitand comparing detected concentrations of drug against a standard curve.A reduction in drug recovery was correlated to an impact on physicaldrug conformation resulting in reduced detection by the ELISA kit. Ifthe jet dispensing had no impact on drug conformation, the concentrationof the drug recovered from the device would have been the same as thepositive control. If damage occurred, the concentration detected wouldhave been similar to the negative control. The test matrix is shown inTable 10.

TABLE 10 Sample Number of times replicated Description Negative control3 Novolog (undiluted; inactivated with repeated boiling and freeze/thawcycles) Positive control 3 Novolog hand dispensed with standard syringeJet test (150 psi) 5* Maximum psi jet delivery of undiluted Novolog intocollection tube Jet test (hand dispense) 3 Minimum PSI jet delivery ofundiluted Novolog into collection tube * one outlier data point removed

The test method is illustrated in FIG. 88 . The assay principle isillustrated in FIG. 89 . The results are shown in Table 11. Thestatistics are shown in Table 12.

TABLE 11 Sample Description Mean Recovery (mU/mL) ± Standard Deviation%CV Negative control Novolog (undiluted; inactivated with 7.99E+052.408E+05 30.14% repeated boiling and freeze/thaw cycles) Positivecontrol Novolog hand dispensed with standard syringe 1.47E+07 3.765E+0625.58% Jet test (150 psi) Maximum psi jet delivery of undiluted Novologinto collection tube 2.11E+07 1.490E+06 7.06% Jet test (hand dispense)Minimum PSI jet delivery of undiluted Novolog into collection tube2.13E+07 1.909E+06 8.98%

TABLE 12 Statistics (Student’s T-test, 2 tailed, non-pair-wise, forsignificance p<0.05) Test P Significance NC v. PC 0.021296 S JT_(max) v.JT_(min) 0.710398 N/S PC v. JT_(max) 0.184357 N/S PC v. JT_(min)0.070188 N/S

The assay was able to demonstrate detection of a physically inactivateddrug by this method and that this is significantly different than apositive control. Within the context of the test parameters of thisexperiment, there was no negative impact on drug conformation whendispensed through the jet delivery system at 150 psi. Within the contextof the test parameters of this experiment, there was no negative impacton drug conformation when dispensed through the jet delivery system at<30 psi. There was no significant (p >0.7) difference between dispensingat 150 psi or <30 psi through the jet system. There was no significantdifference compared to the positive control at either pressure.

OTHER EMBODIMENTS

While certain embodiments have been described, the disclosure is notlimited to such embodiments.

As an example, in some embodiments, an elastomeric bladder can be usedto contain a dispensable substance (e.g., a therapeutic agent) such thatthe dispensable substance is dispensed form the ingestible device viathe compressive forces of the elastomeric bladder, when stretched, and avalve system.

FIG. 90 illustrates an ingestible device 9000 having a housing 9010.Ingestible device also has an elastomeric bladder 9002 and a valvesystem 9004. The ingestible device 9000 further includes a tube 9006,connecting a dispensing port 9008 to bladder 9002. In addition,ingestible device 9000 has a PCBA 9012. Initially, the elastomericbladder 9002 contains a volume of a dispensable substance and stretchesto accommodate the volume of dispensable substance. The stretchedbladder 9002 exerts a compressive force on the dispensable substance, sothat, ultimately, the dispensable substance exits the bladder 9002through tube 9006, and finally through the dispensing port 9008 in thehousing 9010. Valve system 9004 is disposed on or in the tube 9006 andhas two positions, closed and open. When closed, valve system 9004prevents fluid communication between bladder 9002 and dispensing port9008. In the closed position, valve system 9004 fully obstructs the flowin tube 9006. In the open position, valve system 9004 facilitates fluidcommunication between bladder 9002 and dispensing port 9008. In the openposition, valve system 9004 removes at least part of the obstructionfrom tube 9006. As a result, the compressive force of bladder 9002presses the dispensable substance from bladder 9002, through tube 9006and opens valve system 9004. The dispensable substance then dispensesonto a section of the GI tract from dispensing port 9008, as desired.Valve system 9004 is controlled by PCBA 9012. In general, PCBA 9012 isconfigured to receive a signal and actuate valve system 9004 based onthe information contained in the received signal. PCBA 9012 mayadditionally power the valve system.

Elastomeric bladder 9002 may be made of any appropriate material.Generally, bladder 9002 is made of an elastomeric material. Exemplarymaterials include latex, silicone, PVC, rubber, low densitypolyethylene, polypropylene. Typically, bladder 9002 has a thicknessthat provides the desired flexibility. In some embodiments, bladder 9002has a thickness of from 0.001 inch to 0.0020 inch (e.g., 0.002 inch to.0015 inch).

FIGS. 91 and 92A illustrate a wax valve system 9100 as an embodiment ofvalve system 9004. The wax valve system 9100 includes a diaphragm 9102,wax 9104, and a heating element 9106. Typically, heating element 9106 isin electronic communication with PCBA 9012, also shown in FIG. 90 . Wax9102 is solid and is completely covered by diaphragm 9102. Theconfiguration of wax 9104 protrudes fully into tube 9006 so that noliquid or gas may pass through tube 9006. Diaphragm 9102 is stretcheddue to the configuration of wax 9104, however the natural state ofdiaphragm 9102 obstructs part or none of tube 9006. Wax valve system9100 is considered closed when wax 9104 and stretched diaphragm 9102fully obstructs tube 9006. Heating element 9106 is thermally coupled towax 9104 so that when heating element 9106 produces heat, wax 9104melts. As wax 9104 melts, the pressure from wax 9104 to stretchdiaphragm 9102 decreases and diaphragm 9102 relaxes to a more naturalstate. Diaphragm 9102 and wax 9104 no longer fully obstruct tube 9006,and wax valve system 9100 is considered open.

FIGS. 92A and 92B show wax valve system 9100 in ingestible device 9000.In FIG. 92A wax valve system 9100 is closed, and in FIG. 92B wax valvesystem 9100 is open.

In FIG. 92A, bladder 9002 is stretched and contains dispensablesubstance. Bladder 9002 applies a compressive force on the dispensablesubstance so that is exits bladder 9002 through tube 9006. Wax valvesystem 9100 is in the closed position and bladder 9002 cannot compress.Wax 9104 supports diaphragm 9102 so that diaphragm 9102 stretches toobstruct tube 9006, preventing fluid communication between bladder 9002and dispensing port 9008. Wax valve system 9100 is closed and thedispensable substance cannot be dispensed through dispensing port 9008.

PCBA 9012 then receives a signal to dispense the dispensable substanceand sends an electrical current to heating element 9106. Heating element9106 melts wax 9104. As a result, diaphragm 9102 is no longer supportedby wax 9104, and relaxes from the obstructive, stretched position, to aneutral position, shown in FIG. 92B. In the neutral position, diaphragm9102 may partially obstruct tube 9006 or it may obstruct none of tube9006. The neutral position shown in FIG. 92B shows diaphragm 9102partially obstructing tube 9006. When wax valve system 9100 opens, dueto the relaxing of diaphragm 9102, bladder 9002 is in fluidcommunication with dispensing port 9008, also shown in FIG. 92B. Thecompressive force of bladder 9002 on the dispensable substance, pressesthe dispensable substance through tube 9006, open wax valve system 9100,and dispensing port 9008, into the GI tract, as desired. Bladder 9002 isfully compressed and may contain a residual volume of dispensablesubstance.

While certain embodiments have been described in which an ingestibledevice includes a single outlet, e.g. nozzle, the disclosure is notlimited in this regard. In general, any of the embodiments of aningestible device disclosed herein can be implemented with multipleoutlets, e.g., nozzles. For example, an ingestible device may includetwo outlets, three outlets, four outlets, five outlets or more than fiveoutlets. In such embodiments, the same type of delivery mechanism (e.g.,gas generating cell) can be used for each outlet (e.g., nozzle),different types of delivery mechanisms can be used for differentoutlets, or a combination may be used. In some embodiments, theingestible device may include a separate storage reservoir for eachdispensable substance, the ingestible device may include a separatedelivery system for each storage reservoir, or a combination of suchapproaches can be used. In certain embodiments, an ingestible devicewith multiple outlets is designed so that each outlet opens at the sametime. Such an approach can enhance relatively high pressure delivery ofthe dispensable substance(s), which such relatively high pressure isdesirable. In certain embodiments, using multiple outlets (e.g., twooutlets) the amount of dispensable substance delivered to tissue of theGI tract (e.g., between the muscularis externa and the submucosal layer)can be increased. In some embodiments, using multiple outlets (e.g., twooutlets) can allow for enhancement of force balancing (e.g., the jet ofdispensable substance has a reduced tendency to case the ingestibledevice to move away from a desired location, such as the intestinalwall). In some embodiments, using multiple outlets (e.g., two outlets)can lead to an enhanced probability of delivering some dose ofdispensable substance in the case where the ingestible device is locatedat a location relatively remote from the target location.

FIG. 93 illustrates an exemplary embodiment of an ingestible device93000 including a first outlet 93100A and a second outlet 93100B. Device93000 also includes a piston 93200 sealed with an O-ring 93300 and anenergy source (e.g., a gas generating cell) 93400 to move piston 93200.In addition, device 93000 includes a storage reservoir 93500 and a cap93600. During use, energy source 93400 causes piston 93200 to move,forcing the dispensable substance in storage reservoir 93500 to exitdevice 93100 via outlets 93100A and 93100B.

A nozzle can be designed as appropriate. Examples of nozzle designsinclude nozzles that have straight sidewalls and nozzles that havetapered sidewalls. Examples of nozzles with tapered sidewalls areillustrated, for example, in FIGS. 31, 32, 45, 46A, 47, and 49-63 .

While certain volumes for a storage reservoir have been disclosed, thedisclosure is not limited to such volumes. Generally, a storagereservoir can have a volume as desired. For example, in any of theembodiments disclosed herein, a storage reservoir may have a volume offrom 10 µL to 1500 µL (e.g., from 50 µL to 1000 µL, from 100 µL to 750µL, from 200 _(V)L to 600 µL, from 300 µL to 500 µL, from 350 µL to 450µL, 400 µL).

In any embodiment, an ingestible device may include one or more storagereservoirs for containing a sample. For example, an ingestible devicecan be configured to obtain a sample while in the GI tract of a subject.

The various embodiments of systems, processes and apparatuses have beendescribed herein by way of example only. It is contemplated that thefeatures and limitations described in any one embodiment may be appliedto any other embodiment herein, and flowcharts or examples relating toone embodiment may be combined with any other embodiment in a suitablemanner, done in different orders, or done in parallel. It should benoted, the systems and/or methods described above may be applied to, orused in accordance with, other systems and/or methods. Variousmodifications and variations may be made to these example embodimentswithout departing from the spirit and scope of the embodiments, and theappended listing of embodiments should be given the broadestinterpretation consistent with the description as a whole.

We claim:
 1. An ingestible device, comprising: a dispensable substancewithin a housing; at least one nozzle in the housing; a force generatorin the housing configured to exert pressure on the dispensablesubstance; and a burst disk having a first state wherein the burst diskprevents the dispensable substance from moving out of the housing andthe burst disk having a second state wherein the burst disk allows thedispensable substance to move out of the housing through the nozzleunder pressure exerted by the force generator.
 2. The ingestible deviceof claim 1 wherein the force generator generates a pressure in thedispensable substance sufficient to change the burst disk to the secondstate and to drive a jet of the dispensable substance out of the nozzleafter the ingestible device is ingested and the burst disk is in thesecond state.
 3. The ingestible device of claim 1 wherein the nozzleextends radially outward through a sidewall of the housing in adirection perpendicular to a longitudinal axis of the housing.
 4. Theingestible device of claim 1 comprising a plurality of nozzles radiallyspaced apart to balance reaction forces.
 5. The ingestible device ofclaim 1 wherein the dispensable substance is in a storage reservoirformed between a slidable piston and inner walls of the housing.
 6. Theingestible device of claim 1 wherein the force generator generates apressure of 100-360 psi in the dispensable substance.
 7. An ingestibledevice, comprising: a dispensable substance within a housing; one ormore nozzles in the housing; a force generator in the housing; and abioabsorbable plug in each nozzle, the bioabsorbable plug having a firststate configured to prevent the dispensable substance from exiting theingestible device via the nozzle, and the bioabsorbable plug having asecond state configured to allow the dispensable substance to move outof the ingestible device in a jet through the nozzle under pressureexerted on the dispensable substance by the force generator.
 8. Theingestible device of claim 7 wherein the bioabsorbable plug comprises anenteric material.
 9. The ingestible device of claim 7 wherein thebioabsorbable plug dissolves in the presence of intestinal luminalfluid.
 10. The ingestible device of claim 7 wherein the nozzle extendsradially outward through a sidewall of the housing in a directionperpendicular to a longitudinal axis of the housing.
 11. The ingestibledevice of claim 7 comprising a plurality of nozzles radially equallyspaced apart.
 12. The ingestible device of claim 7 wherein thedispensable substance is in a storage reservoir formed between aslidable piston and inner walls of the housing.
 13. The ingestibledevice of claim 7 wherein the force generator generates a pressure of100-360 psi in the dispensable substance.
 14. An ingestible device,comprising: a storage reservoir in a housing, the storage reservoirholding a dispensable substance, the storage reservoir formed between aslidable piston and inner walls of the housing; one or more nozzles inthe housing, each nozzle extending radially outward through a sidewallof the housing in a direction perpendicular to a longitudinal axis ofthe housing; a force generator in the housing configured to pressurizethe dispensable substance after the ingestible device is ingested; andan occluder having a first state configured to prevent the dispensablesubstance from exiting the ingestible device via the nozzles and theoccluder having a second state configured to allow the dispensablesubstance to exit the ingestible device from each of the nozzles in ajet capable of penetrating a mucosa or epithelial layer of smallintestines.
 15. The ingestible device of claim 14 wherein the forcegenerator exerts force on the slidable piston which generates a pressureof 100-360 psi in the dispensable substance.
 16. The ingestible deviceof claim 14 comprising a plurality of nozzles equally spaced apart.